WO2003060071A2 - Albumin fusion proteins - Google Patents

Albumin fusion proteins Download PDF

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Publication number
WO2003060071A2
WO2003060071A2 PCT/US2002/040891 US0240891W WO03060071A2 WO 2003060071 A2 WO2003060071 A2 WO 2003060071A2 US 0240891 W US0240891 W US 0240891W WO 03060071 A2 WO03060071 A2 WO 03060071A2
Authority
WO
WIPO (PCT)
Prior art keywords
variant
fragment
albumin
protein
albumin fusion
Prior art date
Application number
PCT/US2002/040891
Other languages
English (en)
French (fr)
Other versions
WO2003060071A3 (en
Inventor
David James Ballance
Andrew John Turner
Craig A. Rosen
William A. Haseltine
Original Assignee
Human Genome Sciences, Inc.
Delta Biotechnology Limited
Principia Pharmaceutical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27586544&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2003060071(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to SI200231033T priority Critical patent/SI1463751T1/sl
Priority to EP02799966.3A priority patent/EP1463751B1/en
Priority to ES02799966T priority patent/ES2425738T3/es
Priority to CA2471363A priority patent/CA2471363C/en
Priority to JP2003560158A priority patent/JP5424521B2/ja
Priority to AU2002364586A priority patent/AU2002364586A1/en
Priority to DK02799966.3T priority patent/DK1463751T3/da
Application filed by Human Genome Sciences, Inc., Delta Biotechnology Limited, Principia Pharmaceutical Corporation filed Critical Human Genome Sciences, Inc.
Publication of WO2003060071A2 publication Critical patent/WO2003060071A2/en
Priority to US10/775,204 priority patent/US7141547B2/en
Publication of WO2003060071A3 publication Critical patent/WO2003060071A3/en
Priority to KR1020127015659A priority patent/KR101271635B1/ko
Priority to US11/429,373 priority patent/US7238667B2/en
Priority to US11/429,374 priority patent/US7847079B2/en
Priority to US11/429,276 priority patent/US7592010B2/en
Priority to US11/495,624 priority patent/US20080004206A1/en
Priority to US11/714,841 priority patent/US20070244047A1/en
Priority to US11/783,419 priority patent/US20070259815A1/en
Priority to US11/772,643 priority patent/US7799759B2/en
Priority to US11/929,946 priority patent/US20090099073A1/en
Priority to US11/929,702 priority patent/US20090093402A1/en
Priority to US11/929,828 priority patent/US8012464B2/en
Priority to US11/929,714 priority patent/US20080161243A1/en
Priority to US11/929,912 priority patent/US20080167238A1/en
Priority to US11/929,939 priority patent/US8211439B2/en
Priority to US11/929,953 priority patent/US20080167240A1/en
Priority to US11/932,823 priority patent/US20080194481A1/en
Priority to US12/793,652 priority patent/US20100291033A1/en
Priority to US12/793,658 priority patent/US8287859B2/en
Priority to US12/836,447 priority patent/US8071539B2/en
Priority to US13/078,708 priority patent/US8252739B2/en
Priority to US13/078,827 priority patent/US8513189B2/en
Priority to US13/929,310 priority patent/US8993517B2/en
Priority to US13/966,186 priority patent/US20140179596A1/en
Priority to CY2014040C priority patent/CY2014040I2/el
Priority to US14/611,810 priority patent/US9221896B2/en
Priority to US14/818,972 priority patent/US9296809B2/en
Priority to US15/041,517 priority patent/US20160152687A1/en
Priority to US15/381,347 priority patent/US20170096472A1/en

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Definitions

  • the invention relates generally to Therapeutic proteins (including, but not limited to, at least one polypeptide, antibody, peptide, or fragment and variant thereof) fused to albumin or fragments or variants of albumin.
  • the invention encompasses polynucleotides encoding therapeutic albumin fusion proteins, therapeutic albumin fusion proteins, compositions, pharmaceutical compositions, formulations and kits.
  • Host cells transformed with the polynucleotides encoding therapeutic albumin fusion proteins are also encompassed by the invention, as are methods of making the albumin fusion proteins of the invention using these polynucleotides, and/or host cells.
  • HSA Human serum albumin
  • HA a protein of 585 amino acids in its mature form (as shown in Figure 1 (SEQ ID NO: 1038))
  • SEQ ID NO: 1038 Human serum albumin
  • rHA recombinant HA
  • the present invention encompasses albumin fusion proteins comprising a
  • Therapeutic protein e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof fused to albumin or a fragment (portion) or variant of albumin.
  • the present invention also encompasses polynucleotides comprising, or alternatively consisting of, nucleic acid molecules encoding a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof) fused to albumin or a fragment (portion) or variant of albumin.
  • the present invention also encompasses polynucleotides, comprising, or alternatively consisting of, nucleic acid molecules encoding proteins comprising a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof) fused to albumin or a fragment (portion) or variant of albumin, that is sufficient to prolong the shelf life of the Therapeutic protein, and/or stabilize the Therapeutic protein and/or its activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo.
  • a Therapeutic protein e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof
  • Albumin fusion proteins encoded by a polynucleotide of the invention are also encompassed by the invention, as are host cells transformed with polynucleotides of the invention, and methods of making the albumin fusion proteins of the invention and using these polynucleotides of the invention, and/or host cells.
  • albumin fusion proteins include, but are not limited to, those encoded by the polynucleotides described in Table 2.
  • the invention also encompasses pharmaceutical formulations comprising an albumin fusion protein of the invention and a pharmaceutically acceptable diluent or carrier. Such formulations may be in a kit or container. Such kit or container may be packaged with instructions pertaining to the extended shelf life of the Therapeutic protein. Such formulations may be used in methods of treating, preventing, ameliorating or diagnosing a disease or disease symptom in a patient, preferably a mammal, most preferably a human, comprising the step of administering the pharmaceutical formulation to the patient.
  • the present invention encompasses methods of preventing, treating, or ameliorating a disease or disorder.
  • the present invention encompasses a method of treating a disease or disorder listed in the "Preferred Indication: Y" column of Table 1 comprising administering to a patient in which such treatment, prevention or amelioration is desired an albumin fusion protein of the invention that comprises a Therapeutic protein or portion corresponding to a Therapeutic protein (or fragment or variant thereof) disclosed in the "Therapeutic Protein: X" column of Table 1 (in the same row as the disease or disorder to be treated is listed in the "Preferred Indication: Y" column of Table 1) in an amount effective to treat, prevent or ameliorate the disease or disorder.
  • an albumin fusion protein described in Table 1 or 2 has extended shelf life.
  • an albumin fusion protein described in Table 1 or 2 is more stable than the corresponding unfused Therapeutic molecule described in Table 1.
  • the present invention further includes transgenic organisms modified to contain the nucleic acid molecules of the invention (including, but not limited to, the polynucleotides described in Tables 1 and 2), preferably modified to express an albumin fusion protein of the invention.
  • Figure 1 A-D shows the amino acid sequence of the mature form of human albumin (SEQ ID NO:1038) and a polynucleotide encoding it (SEQ ID NO:1037).
  • Figure 2 shows the restriction map of the pPPC0005 cloning vector ATCC deposit PTA-3278.
  • Figure 3 shows the restriction map of the pSAC35 yeast S. cerevisiae expression vector (Sleep et al., BioTechnology 8:42 (1990)).
  • FIG 4 shows the effect of various dilutions of EPO albumin fusion proteins encoded by DNA comprised in Construct ID NOS. (hereinafter CID) 1966 and 1981 and recombinant human EPO on the proliferation of TF-1 cells (see Examples 8 and 9).
  • CID Construct ID NOS.
  • TF-1 cells see Examples 8 and 9.
  • Cells were washed 3X to remove GM-CSF and plated at 10,000 cells/well for 72 hours in the presence of 3 -fold dilutions of CID 1966 protein or CID 1981 protein. Concentrations used were calculated based on the weight of Epo alone, not HSA plus Epo.
  • Epo (rhEpo) was used as the positive control and serially diluted 3 fold from 100 ng/ml to
  • Figure 5 is a dose response analysis and shows the effect of various doses of recombinant human EPO and EPO albumin fusion proteins encoded by DNA comprised in
  • CID 1966 and 1981 on the percent change in hematocrit from day 0 to day 7 (see Examples 8 and 9).
  • 48 eight-week old female DBA/2NHsd mice were divided into 12 groups of 4 animals each.
  • Recombinant human Epo (rhEpo) was administered subcutaneously at 0.5, 1.5, 4.5 and 12 ⁇ g/kg on days 0, 2, 4, and 6.
  • Epo albumin fusion proteins made from constructs CID 1966 and CID 1981 were administered subcutaneously at 2, 6, 18, and 54 ⁇ g/kg on days 0, 2, 4, and 6.
  • Epo albumin fusion proteins allow a rough equimolar comparison with recombinant human Epo (note that the weight of the fusions is about 4.35 times the weight of non-glycosylated Epo).
  • the animals were bled via a tail vein and the hematocrit was determined by centrifugation. ( ⁇ ) rhEpo; (o) CID 1981; (A) CID 1966.
  • Figure 7 shows the effect of various dilutions albumin fusion proteins encoded by DNA comprised in CID 1981 and 1997, respectively, on the proliferation of TF-1 cells (see Examples 9 and 10).
  • Cells were washed 3X to remove GM-CSF and plated at 10,000 cells/well for 72 hours in the presence of 3-fold dilutions of Epo albumin fusion proteins encoded by CID 1981 or 1997.
  • Equimolar amounts of rhEpo were used as a positive control (4.35 times less protein added since weight of non-glycosylated Epo is 20 kd, while Epo albumin fusion proteins are 87 kd).
  • Cells were exposed to 0.5 ⁇ Ci/well of 3 H-thymidine for an additional 24 hours.
  • A CID 1981 (CHO);
  • Figure 8 shows the effect of various doses of recombinant human EPO
  • Figure 9 shows the effect of various dilutions of IL2 albumin fusion proteins encoded by DNA comprised in CID 1812 (see Example 15) on CTLL-2 proliferation.
  • lxlO 4 cells/well were seeded in a 96-well plate in a final volume of 200 ul of complete medium containing the indicated amount of IL2 albumin fusion protein (CID 1812). All samples were run in triplicate. The cells were incubated for 40 hours at 37°C, then 20 ul of Alamar Blue was added and cells incubated for 8 hours. Absorbance at 530/590 was used as a measure of proliferation.
  • FIG 10 shows the effect of IL2 albumin fusion protein encoded by DNA comprised in CID 1812 on RENCA tumor growth at day 21 (see Example 15).
  • BALB/c mice (n-10) were injected SC (midflank) with 10 5 RENCA cells. 10 days later mice received 2 cycles (Day 10 to Day 14 and Days 17-21) of daily (QD) injections of rIL2 (0.9 mg/kg), IL2 albumin fusion protein (CID 1812 protein; 0.6 mg/kg), or PBS (Placebo) or injections every other day (QOD) of CID 1812 protein (0.6 mg/kg).
  • QD daily
  • rIL2 0.9 mg/kg
  • CID 1812 protein IL2 albumin fusion protein
  • PBS Placebo
  • injections every other day (QOD) of CID 1812 protein 0.6 mg/kg.
  • the tumor volume was determined on Day 21 after RENCA inoculation. The data are presented in scatter analysis (each dot representing single animal).
  • FIG 11 shows the effect of various dilutions of GCSF albumin fusion proteins encoded by DNA comprised in CID 1642 and 1643 on NFS-60 cell proliferation (see Examples 19 and 20).
  • ( ⁇ ) CID 1642;
  • (A) CID 1643;
  • (O) HSA.
  • Figure 12 shows the effect of recombinant human GCSF (Neupogen) and
  • GCSF albumin fusion protein on total white blood cell count (see Example 19). Total WBC (10 cells/ul) on each day are presented as the group mean ⁇ SEM. GCSF albumin fusion protein was administered sc at either 25 or 100 ug/kg every 4 days x 4 (Q4D) , or at 100 ug/kg every 7 days x 2 (Q7D). Data from Days 8 and 9 for GCSF albumin fusion protein 100 ug/kg Q7 are presented as Days 9 and 10, respectively, to facilitate comparison with other groups. Controls were saline vehicle administered SC every 4 days x 4 (Vehicle Q4D), or Neupogen administered SC daily x 14 (Neupogen 5 ug/kg QD). The treatment period is considered Days 1-14, and the recovery period, Days 15-28.
  • Figure 13 shows the effect of various dilutions of IFNb albumin fusion proteins encoded by DNA comprised in CID 2011 and 2053 on SEAP activity in the ISRE- SEAP/293F reporter cells (see Example 25). Proteins were serially diluted from 5e-7 to le- 14 g/ml in DMEM/10% FBS and used to treat ISRE-SEAP/293F reporter cells. After 24 hours supernatants were removed from reporter cells and assayed for SEAP activity. IFNb albumin fusion protein was purified from three stable clones: 293F/#2011, CHO/#2011 and NSO/#2053. Mammalian derived IFNb, Avonex, came from Biogen and was reported to have a specific activity of 2.0e5 IU/ug.
  • Figure 14 illustrates the steady-state levels of insulin mRNA in INS-1 (832/13) cells after treatment with GLP-1 or GLP-1 albumin fusion protein encoded by construct ID
  • CID 3070 protein Both GLP-1 and the CID 3070 protein stimulate transcription of the insulin gene in INS-1 cells.
  • Figure 15 compares the anti-proliferative activity of IFN albumin fusion protein encoded by CID 3165 (CID 3165 protein) and recombinant IFNa (rlFNa) on Hs294T melanoma cells.
  • the cells were cultured with varying concentrations of either CID 3165 protein or rlFNa and proliferation was measured by BrdU incorporation after 3 days of culture.
  • CID 3165 protein caused measurable inhibition of cell proliferation at concentrations above 10 ng/ml with 50% inhibition achieved at approximately 200 ng/ml.
  • ( ⁇ ) CID 3165 protein
  • ( ⁇ ) rlFNa.
  • Figure 16 shows the effect of various dilutions of IFNa albumin fusion proteins on SEAP activity in the ISRE-SEAP/293F reporter cells.
  • One preparation of IFNa fused upstream of albumin ( ⁇ ) was tested, as well as two different preparations of IFNa fused downstream of albumin (A) and ( ⁇ ).
  • Figure 17 shows the effect of time and dose of IFNa albumin fusion protein encoded by DNA comprised in construct 2249 (CID 2249 protein) on the mRNA level of
  • Figure 18 shows the effect of various dilutions of insulin albumin fusion proteins encoded by DNA comprised in constructs 2250 and 2276 on glucose uptake in 3T3-
  • Figure 19 shows the effect of various GCSF albumin fusion proteins, including those encoded by CID #1643 and #2702 (L-171, see Example 114), on NFS cell proliferation.
  • the horizontal dashed line indicates the minimum level of detection.
  • polynucleotide refers to a nucleic acid molecule having a nucleotide sequence encoding a fusion protein comprising, or alternatively consisting of, at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one Therapeutic protein X (or fragment or variant thereof); a nucleic acid molecule having a nucleotide sequence encoding a fusion protein comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO:Y (as described in column 6 of Table 2) or a fragment or variant thereof; a nucleic acid molecule having a nucleotide sequence comprising or alternatively consisting of the sequence shown in SEQ ID NO:X; a nucleic acid molecule having a nucleotide sequence encoding a fusion protein comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO:Z; a nucleic acid molecule having a nucleotide
  • albumin fusion construct refers to a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof); a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof) generated as described in Table 2 or in the Examples; or a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least -one polynucleot
  • the polynucleotide encoding the Therapeutic protein and albumin protein, once part of the albumin fusion construct, may each be referred to as a "portion," "region” or “moiety” of the albumin fusion construct.
  • the present invention relates generally to polynucleotides encoding albumin fusion proteins; albumin fusion proteins; and methods of treating, preventing, or ameliorating diseases or disorders using albumin fusion proteins or polynucleotides encoding albumin fusion proteins.
  • albumin fusion protein refers to a protein formed by the fusion of at least one molecule of albumin (or a fragment or variant thereof) to at least one molecule of a Therapeutic protein (or fragment or variant thereof).
  • An albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or a portion of a Therapeutic protein is joined in- frame with a polynucleotide encoding all or a portion of albumin).
  • the Therapeutic protein and albumin protein, once part of the albumin fusion protein may each be referred to as a "portion", "region” or "moiety" of the albumin fusion protein (e.g., a "Therapeutic protein portion" or an "albumin protein portion”).
  • an albumin fusion protein of the invention comprises at least one molecule of a Therapeutic protein X or fragment or variant of thereof (including, but not limited to a mature form of the Therapeutic protein X) and at least one molecule of albumin or fragment or variant thereof (including but not limited to a mature form of albumin).
  • an albumin fusion protein of the invention is processed by a host cell and secreted into the surrounding culture medium. Processing of the nascent albumin fusion protein that occurs in the secretory pathways of the host used for expression may include, but is not limited to signal peptide cleavage; formation of disulfide bonds; proper folding; addition and processing of carbohydrates (such as for example, N- and O- linked glycosylation); specific proteolytic cleavages; and assembly into multimeric proteins.
  • An albumin fusion protein of the invention is preferably in the processed form.
  • the "processed form of an albumin fusion protein” refers to an albumin fusion protein product which has undergone N- terminal signal peptide cleavage, herein also referred to as a "mature albumin fusion protein”.
  • a representative clone containing an albumin fusion construct of the invention was deposited with the American Type Culture Collection (herein referred to as "ATCC®"). Furthermore, it is possible to retrieve a given albumin fusion construct from the deposit by techniques known in the art and described elsewhere herein.
  • the ATCC® is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA.
  • the ATCC® deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.
  • the invention provides a polynucleotide encoding an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a serum albumin protein, h a further embodiment, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a serum albumin protein.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a serum albumin protein encoded by a polynucleotide described in Table 2.
  • the invention provides a polynucleotide encoding an albumin fusion protein whose sequence is shown as SEQ ID NO:Y in Table 2.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment of a Therapeutic protein and a serum albumin protein.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active variant of a Therapeutic protein and a serum albumin protein, preferred embodiments, the serum albumin protein component of the albumin fusion protein is the mature portion of serum albumin.
  • the invention further encompasses polynucleotides encoding these albumin fusion proteins.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein, and a biologically active and/or therapeutically active fragment of serum albumin.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a biologically active and/or therapeutically active variant of serum albumin.
  • the Therapeutic protein portion of the albumin fusion protein is the mature portion of the Therapeutic protein, hi a further preferred embodiment, the Therapeutic protein portion of the albumin fusion protein is the extracellular soluble domain of the Therapeutic protein.
  • the Therapeutic protein portion of the albumin fusion protein is the active form of the Therapeutic protein.
  • the invention further encompasses polynucleotides encoding these albumin fusion proteins.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment or variant of a Therapeutic protein and a biologically active and/or therapeutically active fragment or variant of serum albumin.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of a Therapeutic protein and the mature portion of serum albumin.
  • the invention further encompasses polynucleotides encoding these albumin fusion proteins.
  • a polynucleotide of the invention encodes a protein comprising or alternatively consisting of, at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion.
  • An additional embodiment includes a polynucleotide encoding a protein comprising or alternatively consisting of at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are linked with one another by chemical conjugation.
  • Therapeutic protein refers to proteins, polypeptides, antibodies, peptides or fragments or variants thereof, having one or more therapeutic and/or biological activities.
  • Therapeutic proteins encompassed by the invention include but are not limited to, proteins, polypeptides, peptides, antibodies, and biologies. (The terms peptides, proteins, and polypeptides are used interchangeably herein.) It is specifically contemplated that the term “Therapeutic protein” encompasses antibodies and fragments and variants thereof.
  • a protein of the invention may contain at least a fragment or variant of a
  • Therapeutic protein and/or at least a fragment or variant of an antibody. Additionally, the term “Therapeutic protein” may refer to the endogenous or naturally occurring correlate of a
  • therapeutically active is meant a polypeptide that possesses one or more known biological and/or therapeutic activities associated with a therapeutic protein such as one or more of the
  • a "Therapeutic protein” is a protein that is useful to treat, prevent or ameliorate a disease, condition or disorder.
  • a "Therapeutic protein” may be one that binds specifically to a particular cell type (normal (e.g., lymphocytes) or abnormal e.g., (cancer cells)) and therefore may be used to target a compound (drug, or cytotoxic agent) to that cell type specifically.
  • albumin fusion protein of the invention includes, but is not limited to, erythropoietin (EPO), IL-2, G-CSF, Insulin, Calcitonin, Growth Hormone, IFN-alpha,
  • IFN-beta PTH, TR6 (International Publication No. WO 98/30694), BLyS, BLyS single chain antibody, Resistin, Growth hormone releasing factor, VEGF-2, KGF-2, D-SLAM, KDI, and
  • Interferon hybrids may also be fused to the amino or carboxy terminus of albumin to form an interferon hybrid albumin fusion protein.
  • Interferon hybrid albumin fusion protein may have enhanced, or alternatively, suppressed interferon activity, such as antiviral responses, regulation of cell growth, and modulation of immune response (Lebleu et al., PNAS USA, 73:3107-3111 (1976); Gresser et al., Nature, 251 :543-545 (1974); and
  • Each interferon hybrid albumin fusion protein can be used to treat, prevent, or ameliorate viral infections ⁇ e.g., hepatitis (e.g.,
  • HCV HCV
  • HIV HIV
  • multiple sclerosis or cancer.
  • the interferon hybrid portion of the interferon hybrid albumin fusion protein comprises an interferon alpha-interferon alpha hybrid (herein referred to as an alpha-alpha hybrid).
  • the alpha-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha A fused to interferon alpha D.
  • the A D hybrid is fused at the common Bgi ⁇ restriction site to interferon alpha D, wherein the N-terminal portion of the A D hybrid corresponds to amino acids 1-62 of interferon alpha A and the C-terminal portion corresponds to amino acids 64-166 of interferon alpha D.
  • this A/D hybrid would comprise the amino acid sequence:
  • the A D hybrid is fused at the common Pvui ⁇ restriction site, wherein the N-terminal portion of the A/D hybrid corresponds to amino acids
  • interferon alpha A 1-91 of interferon alpha A and the C-terminal portion corresponds to amino acids 93-166 of interferon alpha D.
  • this A/D hybrid would comprise the amino acid sequence:
  • the alpha-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha A fused to interferon alpha F.
  • the A F hybrid is fused at the common PvuDI restriction site, wherein the N-terminal portion of the A/F hybrid corresponds to amino acids
  • interferon alpha A 1-91 of interferon alpha A and the C-terminal portion corresponds to amino acids 93-166 of interferon alpha F.
  • this A/F hybrid would comprise the amino acid sequence:
  • the alpha-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha A fused to interferon alpha B. h an additional embodiment, the A/B hybrid is fused at the common
  • this A B hybrid would comprise an amino acid sequence:
  • the interferon hybrid portion of the interferon hybrid albumin fusion protein comprises an interferon beta-interferon alpha hybrid (herein referred to as a beta-alpha hybrid).
  • the beta-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon beta-1 fused to interferon alpha D (also referred to as interferon alpha-1).
  • the beta-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon beta-1 fused to interferon alpha D (also referred to as interferon alpha-1).
  • the beta-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon beta-1 fused to interferon alpha D (also referred to as interferon alpha-1).
  • the beta-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon beta-1 fused to interferon al
  • this beta-1/alpha D hybrid would comprise an amino acid sequence:
  • the interferon hybrid portion of the interferon hybrid albumin fusion protein comprises an interferon alpha-interferon beta hybrid (herein referred to as a alpha-beta hybrid).
  • a alpha-beta hybrid an interferon alpha-interferon beta hybrid
  • the alpha-beta hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha D (also referred to as interferon alpha-1) fused to interferon beta-1.
  • the alpha D/beta-1 hybrid is fused wherein the N-terminal portion corresponds to amino acids 1-
  • interferon alpha D and the C-terminal portion corresponds to amino acids 74-166 of interferon beta-1.
  • this alpha D/beta-1 hybrid would have an amino acid sequence:
  • the interferon hybrid portion of the interferon hybrid albumin fusion proteins may comprise additional combinations of alpha-alpha interferon hybrids, alpha-beta interferon hybrids, and beta-alpha interferon hybrids, hi additional embodiments, the interferon hybrid portion of the interferon hybrid albumin fusion protein may be modified to include mutations, substitutions, deletions, or additions to the amino acid sequence of the interferon hybrid. Such modifications to the interferon hybrid albumin fusion proteins may be made, for example, to improve levels of production, increase stability, increase or decrease activity, or confer new biological properties.
  • interferon hybrid albumin fusion proteins are encompassed by the invention, as are host cells and vectors containing polynucleotides encoding the polypeptides.
  • a interferon hybrid albumin fusion protein encoded by a polynucleotide as described above has extended shelf life.
  • a interferon hybrid albumin fusion protein encoded by a polynucleotide described above has a longer serum half-life and/or more stabilized activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo than the corresponding unfused interferon hybrid molecule.
  • a "Therapeutic protein” is a protein that has a biological activity, and in particular, a biological activity that is useful for treating, preventing or ameliorating a disease.
  • a non-inclusive list of biological activities that may be possessed by a Therapeutic protein includes, enhancing the immune response, promoting angiogenesis, inhibiting angiogenesis, regulating endocrine function, regulating hematopoietic functions, stimulating nerve growth, enhancing an immune response, inhibiting an immune response, or any one or more of the biological activities described in the "Biological Activities" section below and/or as disclosed for a given Therapeutic protein in Table 1 (column 2).
  • therapeutic activity or “activity” may refer to an activity whose effect is consistent with a desirable therapeutic outcome in humans, or to desired effects in non-human mammals or in other species or organisms.
  • Therapeutic activity may be measured in vivo or in vitro. For example, a desirable effect may be assayed in cell culture.
  • EPO is the Therapeutic protein
  • the effects of EPO on cell proliferation as described in Example 8 may be used as the endpoint for which therapeutic activity is measured.
  • Such in vitro or cell culture assays are commonly available for many Therapeutic proteins as described in the art. Examples of assays include, but are not limited to those described herein in the Examples section or in the "Exemplary Activity Assay" column
  • Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention are often modified by the attachment of one or more oligosaccharide groups.
  • the modification referred to as glycosylation, can dramatically affect the physical properties of proteins and can be important in protein stability, secretion, and localization. Glycosylation occurs at specific locations along the polypeptide backbone.
  • glycosylation characterized by O-linked oligosaccharides, which are attached to serine or threonine residues; and glycosylation characterized by N-linked oligosaccharides, which are attached to asparagme residues in an Asn-X-Ser or Asn-X-Thr sequence, where X can be any amino acid except proline.
  • N-acetylneuramic acid also known as sialic acid
  • Variables such as protein structure and cell type influence the number and nature of the carbohydrate units within the chains at different glycosylation sites. Glycosylation isomers are also common at the same site within a given cell type.
  • Natural human interferon- ⁇ 2 is O-glycosylated at threonine 106, and N-glycosylation occurs at asparagine 72 in interferon- ⁇ l4 (Adolf et al, J. Biochem 276:511 (1991); Nyman TA et al, J. Biochem 329:295 (1998)).
  • the oligosaccharides at asparagine 80 in natural interferon- ⁇ l ⁇ may play an important factor in the solubility and stability of the protein, but may not be essential for its biological activity.
  • Interferon- ⁇ contains two N-linked oligosaccharide chains at positions 25 and 97, both important for the efficient formation of the bioactive recombinant protein, and having an influence on the pharmacokinetic properties of the protein (Sareneva et al, Eur. J. Biochem 242:191 (1996); Sareneva et al,. Biochem J. 303:831 (1994); Sareneva et al, J. Interferon Res. 13:267 (1993)).
  • N-linked glycosylation occurs at asparagine residues located at positions 24, 38 and 83 while O-linked glycosylation occurs at a serine residue located at position 126 (Lai et al, J. Biol. Chem. 261:3116 (1986); Broudy et al, Arch. Biochem. Biophys. 265:329 (1988)).
  • Glycosylation of EPO albumin fusion proteins may influence the activity and/or stability of the EPO albumin fusion proteins.
  • the EPO portion of the albumin fusion protein may contain 3 N-linked sites for glycosylation, each of which can carry one tetra- antennary structure. When the EPO albumin fusion protein is glycosylated, the half-life of the molecule may be increased. In one embodiment, the EPO albumin fusion protein is glycosylated. In another embodiment, the EPO albumin fusion protein is hyperglycosylated.
  • EPO albumin fusion protein is glycosylated with a carbohydrate group containing sialic acid.
  • the EPO albumin fusion protein comprises a fully sialylated EPO protein containing four sialic acid residues per tetra-antennerary structure per site with a molar ratio of sialic acid to protein 12:1 or greater.
  • the EPO albumin fusion protein comprises a hypersialylated EPO protein wherein one, two, or three sialic acid residues are attached at each tetra-antennerary structure per site with a molar ratio of sialic acid to protein less than 12:1.
  • sialic acid Two types of sialic acid that may be used in the sialylation of the EPO albumin fusion protein are N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid
  • hypersialylated EPO albumin fusion proteins contain
  • the total sialic acid content of hypersialylated EPO albumin fusion proteins is at least 97% Neu5Ac. Most preferred are EPO albumin fusion protein structures with little or no Neu5Gc.
  • the albumin EPO fusion protein has at least 4 moles of sialylation, and more preferably, at least 8-9 moles of sialylation.
  • An additional embodiment comprises an albumin EPO fusion protein with 4 moles of sialylation, 5 moles of sialylation, 6 moles of sialylation, 7 moles of sialylation, 8-9 moles of sialylation, 8 moles of sialylation, 9 moles of sialylation, 10 moles of sialylation, 11 moles of sialylation, or 12 moles of sialylation.
  • the degree of sialylation of a protein changes the charge of the protein and its retention time on a chromatography column. Therefore, certain chromatography steps used in the purification process may be used to monitor or enrich for hypersialylated EPO albumin fusion proteins. In a preferred embodiment, the amount of sialylation may be monitored by
  • EPO albumin fusions may be used to enrich for hypersialylated EPO albumin fusion proteins.
  • the purification steps that may be used to enrich for hypersialylated EPO albumin fusion proteins comprise the butyl-sepharose FF purification step to remove virus particles by high ammonium salt and the hydroxyapatite chromatography at pH 6.8 for the final purification step.
  • Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention may be modified so that glycosylation at one or more sites is altered as a result of manipulation(s) of their nucleic acid sequence, by the host cell in which they are expressed, or due to other conditions of their expression.
  • glycosylation isomers may be produced by abolishing or introducing glycosylation sites, e.g., by substitution or deletion of amino acid residues, such as substitution of glutamine for asparagine, or unglycosylated recombinant proteins may be produced by expressing the proteins in host cells that will not glycosylate them, e.g. in E. coli or glycosylation-deficient yeast.
  • Therapeutic proteins particularly those disclosed in Table 1, and their nucleic acid and amino acid sequences are well known in the art and available in public databases such as Chemical Abstracts Services Databases (e.g., the CAS Registry), GenBank, and subscription provided databases such as GenSeq (e.g., Derwent).
  • Exemplary nucleotide sequences of Therapeutic proteins which may be used to derive a polynucleotide of the invention are shown in column 7, "SEQ ID NO:X,” of Table 2. Sequences shown as SEQ ID NO:X
  • NO:X may be a wild type polynucleotide sequence encoding a given Therapeutic protein
  • sequence may be a variant of said wild type polynucleotide sequence (e.g., a polynucleotide which encodes the wild type
  • Therapeutic protein wherein the DNA sequence of said polynucleotide has been optimized, for example, for expression in a particular species; or a polynucleotide encoding a variant of the wild type Therapeutic protein (i.e., a site directed mutant; an allelic variant)). It is well within the ability of the skilled artisan to use the sequence shown as SEQ ID NO:X to derive the construct described in the same row. For example, if SEQ ID NO:X corresponds to a full length protein, but only a portion of that protein is used to generate the specific CID, it is within the skill of the art to rely on molecular biology techniques, such as PCR, to amplify the specific fragment and clone it into the appropriate vector.
  • SEQ ID NO:X corresponds to a full length protein, but only a portion of that protein is used to generate the specific CID, it is within the skill of the art to rely on molecular biology techniques, such as PCR, to amplify the specific fragment and clone
  • Additional Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention include, but are not limited to, one or more of the Therapeutic proteins or peptides disclosed in the "Therapeutic Protein X" column of Table 1 (column 1), or fragment or variable thereof.
  • Table 1 provides a non-exhaustive list of Therapeutic proteins that correspond to a Therapeutic protein portion of an albumin fusion protein of the invention, or an albumin fusion protein encoded by a polynucleotide of the invention.
  • the first column, "Therapeutic Protein X,” discloses Therapeutic protein molecules that may be followed by parentheses containing scientific and brand names of proteins that comprise, or alternatively consist of, that Therapeutic protein molecule or a fragment or variant thereof.
  • “Therapeutic protein X” as used herein may refer either to an individual Therapeutic protein molecule, or to the entire group of Therapeutic proteins associated with a given Therapeutic protein molecule disclosed in this column.
  • the "Biological activity” column (column 2) describes Biological activities associated with the Therapeutic protein molecule.
  • Example 3 provides references that describe assays which may be used to test the therapeutic and/or biological activity of a Therapeutic proteimX or an albumin fusion protein comprising a Therapeutic protein X (or fragment thereof) portion.
  • Each of the references cited in the "Exemplary Activity Assay” column are herein incorporated by reference in their entireties, particularly with respect to the description of the respective activity assay described in the reference (see Methods section therein, for example) for assaying the corresponding biological activity set forth in the "Biological Activity” column of Table 1.
  • the fourth column describes disease, disorders, and/or conditions that may be treated, prevented, diagnosed, and/or ameliorated by Therapeutic protein X or an albumin fusion protein comprising a Therapeutic protein X (or fragment thereof) portion.
  • the "Construct ID” column (column 5) provides a link to an exemplary albumin fusion construct disclosed in Table 2 which encodes an albumin fusion protein comprising, or alternatively consisting of the referenced Therapeutic Protein X (or fragment thereof) portion.
  • SIGOSIX Chemoprotection; Thrombocytopenia; Viral infections; HIV Infections; Hepatitis; Chronic Hepatitis; Hepatitis B; Chronic Hepatitis B; Hepatitis C; Chronic Hepatitis C; Hepatitis D; Chronic Hepatitis D; Human Papillomaviras; Heipes Simplex Virus Infection; External Condylomata Acuminata; HIV; HIV Infection; Pulmonary Fibrosis; Age-Related Macular Degeneration; Macular Degeneration; Crohn's Disease; Neurological Disorders; Arthritis; Rheumatoid Arthritis; Ulcerative Colitis; Osteoporosis, Osteopenia, Osteoclastogenesis; Fibromyalgia; Sjogren's Syndrome; Chronic Fatigue Syndrome; Fever; Hemmorhagic Fever; Viral Hemmorhagic Fevers; Hyperglycemia; Diabetes; Diabetes Insi
  • Table 2 provides a non-exhaustive list of polynucleotides of the invention comprising, or alternatively consisting of, nucleic acid molecules encoding an albumin fusion protein.
  • the first column, "Fusion No.” gives a fusion number to each polynucleotide.
  • Construct ID provides a unique numerical identifier for each polynucleotide of the invention.
  • the Construct IDs may be used to identify polynucleotides which encode albumin fusion proteins comprising, or alternatively consisting of, a Therapeutic protein portion corresponding to a given Therapeutic Protein:X listed in the corresponding row of
  • column 3 provides the name of a given albumin fusion construct or polynucleotide.
  • an "expression cassette” comprising, or alternatively consisting of, one or more of
  • a polynucleotide encoding a given albumin fusion protein, (2) a leader sequence, (3) a promoter region, and (4) a transcriptional terminator may be assembled in a convenient cloning vector and subsequently be moved into an alternative vector, such as, for example, an expression vector including, for example, a yeast expression vector or a mammalian expression vector.
  • an expression cassette comprising, or alternatively consisting of, a nucleic acid molecule encoding an albumin fusion protein is cloned into pSAC35.
  • an expression cassette comprising, or alternatively consisting of, a nucleic acid molecule encoding an albumin fusion protein is cloned into pC4.
  • a polynucleotide comprising or alternatively consisting of a nucleic acid molecule encoding the
  • Therapeutic protein portion of an albumin fusion protein is cloned into pC4:HSA.
  • an expression cassette comprising, or alternatively consisting of, a nucleic acid molecule encoding an albumin fusion protein is cloned into pEE12.
  • Other useful cloning and/or expression vectors will be known to the skilled artisan and are within the scope of the invention.
  • SEQ ID NO:Y provides the full length amino acid sequence of the albumin fusion protein of the invention.
  • SEQ ID NO:Y shows the unprocessed form of the albumin fusion protein encoded - in other words, SEQ ID NO:Y shows the signal sequence, a HSA portion, and a therapeutic portion all encoded by the particular construct.
  • Specifically contemplated by the present invention are all polynucleotides that encode SEQ ID NO:Y. When these polynucleotides are used to express the encoded protein from a cell, the cell's natural secretion and processing steps produces a protein that lacks the signal sequence listed in columns 4 and/or 11 of Table 2.
  • compositions comprising these two preferred embodiments, including pharmaceutical compositions, are also preferred. Moreover, it is well within the ability of the skilled artisan to replace the signal sequence listed in columns 4 and/or 11 of Table 2 with a different signal sequence, such as those described later in the specification to facilitate secretion of the processed albumin fusion protein.
  • the seventh column provides the parent nucleic acid sequence from which a polynucleotide encoding a Therapeutic protein portion of a given albumin fusion protein may be derived.
  • the parent nucleic acid sequence from which a polynucleotide encoding a Therapeutic protein portion of an albumin fusion protein may be derived comprises the wild type gene sequence encoding a Therapeutic protein shown in Table 1.
  • the parent nucleic acid sequence from which a polynucleotide encoding a Therapeutic protein portion of an albumin fusion protein may be derived comprises a variant or derivative of a wild type gene sequence encoding a
  • Therapeutic protein shown in Table 1 such as, for example, a synthetic codon optimized variant of a wild type gene sequence encoding a Therapeutic protein.
  • SEQ ID NO:Z provides a predicted translation of the parent nucleic acid sequence (SEQ ID NO:X).
  • This parent sequence can be a full length parent protein used to derive the particular construct, the mature portion of a parent protein, a variant or fragment of a wildtype protein, or an artificial sequence that can be used to create the described construct.
  • One of skill in the art can use this amino acid sequence shown in SEQ ID NO:X.
  • SEQ ID NO:Z determines which amino acid residues of an albumin fusion protein encoded by a given construct are provided by the therapeutic protein. Moreover, it is well within the ability of the skilled artisan to use the sequence shown as SEQ ID NO:Z to derive the construct described in the same row. For example, if SEQ ID NO:Z corresponds to a full length protein, but only a portion of that protein is used to generate the specific CID, it is within the skill of the art to rely on molecular biology techniques, such as PCR, to amplify the specific fragment and clone it into the appropriate vector.
  • Amplification primers provided in columns 9 and 10, "SEQ ID NO:A” and “SEQ ID NO:B” respectively, are exemplary primers used to generate a polynucleotide comprising or alternatively consisting of a nucleic acid molecule encoding the Therapeutic protein portion of a given albumin fusion protein.
  • oligonucleotide primers having the sequences shown in columns 9 and/or 10 (SEQ ID NOS:A and/or B) are used to PCR amplify a polynucleotide encoding the Therapeutic protein portion of an albumin fusion protein using a nucleic acid molecule comprising or alternatively consisting of the nucleotide sequence provided in column 7 (SEQ ID NO:X)of the corresponding row as the template DNA.
  • PCR methods are well-established in the art. Additional useful primer sequences could readily be envisioned and utilized by those of ordinary skill in the art.
  • oligonucleotide primers may be used in overlapping PCR reactions to generate mutations within a template DNA sequence. PCR methods are known in the art.
  • an "expression cassette" comprising, or alternatively consisting of one or more of (1) a polynucleotide encoding a given albumin fusion protein, (2) a leader sequence, (3) a promoter region, and (4) a transcriptional terminator can be moved or "subcloned" from one vector into another.
  • Fragments to be subcloned may be generated by methods well known in the art, such as, for example, PCR amplification (e.g., using oligonucleotide primers having the sequence shown in SEQ ID NO:A or B), and/or restriction enzyme digestion.
  • the albumin fusion proteins of the invention are capable of a therapeutic activity and/or biologic activity corresponding to the therapeutic activity and/or biologic activity of the Therapeutic protein corresponding to the Therapeutic protein portion of the albumin fusion protein listed in the corresponding row of Table 1.
  • the therapeutically active protein portions of the albumin fusion proteins of the invention are fragments or variants of the protein encoded by the sequence shown in SEQ ID NO:X column of Table 2, and are capable of the therapeutic activity and/or biologic activity of the corresponding Therapeutic protein.
  • Non-human albumin fusion proteins of growth hormone are included in the specification.
  • the albumin fusion proteins of the invention comprise one or more Serum Albumin proteins of a non-human animal species, fused in tandem and in- frame either at the N-terminus or the C-terminus to one or more Growth Hormone proteins of the same non-human animal species.
  • Non-human Serum Albumin and Growth Hormone proteins are well known in the art and available in public databases.
  • Table 4 presents accession numbers corresponding to non-human Serum Albumin sequences (column 2) and non-human Growth Hormone sequences (column 3) found in GenBank.
  • a Serum Albumin protein from a non-human animal species listed in Table 4 is fused to a Growth Hormone protein from the same non-human animal species.
  • the albumin fusion protein of the invention comprises one or more Bos taurus Serum Albumin proteins listed in Table 4, column 2, fused in tandem and in-frame either at the N-terminus or the C-terminus to one or more Bos taurus Growth Hormone proteins listed in Table 4, column 3.
  • Fusion proteins comprising fragments or variants of non-human Serum
  • Albumin such as, for example, the mature form of Serum Albumin
  • Fusion proteins comprising fragments or variants of non-human Growth Hormone proteins, such as, for example, the mature form of Growth Hormone, are also encompassed by the invention.
  • the non-human Growth Hormone fragments and variants retain growth hormone activity.
  • Polynucleotides of the invention comprise, or alternatively consist of, one or more nucleic acid molecules encoding a non-human albumin fusion protein described above.
  • the polynucleotides can comprise, or alternatively consist of, one or more nucleic acid molecules that encode a Serum Albumin protein from a non-human animal species listed in Table 4, column 1 (such as, for example, the non-human Serum Albumin reference sequences listed in Table 4, column 2) fused in tandem and in-frame either 5' or 3' to a polynucleotide that comprises, or alternatively consists of, one or more nucleic acid molecules encoding the non-human Growth Hormone protein of the corresponding non- human animal species (for example, the Growth Hormone reference sequences listed in Table 4, column 3).
  • non-human albumin fusion proteins are encompassed by the invention, as are host cells and vectors containing these polynucleotides.
  • a non-human albumin fusion protein encoded by a polynucleotide as described above has extended shelf life.
  • a non-human albumin fusion protein encoded by a polynucleotide described above has a longer serum half-life and/or more stabilized activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo than the corresponding unfused Growth Hormone molecule.
  • the present invention also encompasses methods of preventing, treating, or ameliorating a disease or disorder in a non-human animal species.
  • the present invention encompasses a method of treating a veterinary disease or disorder comprising administering to a non-human animal species in which such treatment, prevention or amelioration is desired an albumin fusion protein of the invention that comprises a Growth Hormone portion corresponding to a Growth Hormone protein (or fragment or variant thereof) in an amount effective to treat, prevent or ameliorate the disease or disorder.
  • Veterinary diseases and/or disorders which may be treated, prevented, or ameliorated include growth disorders (such as, for example, pituitary dwarfism), shin soreness, obesity, growth hormone-responsive dermatosis, dilated cardiomyopathy, eating disorders, reproductive disorders, and endocrine disorders.
  • growth disorders such as, for example, pituitary dwarfism
  • shin soreness such as, for example, pituitary dwarfism
  • obesity such as, for example, pituitary dwarfism
  • shin soreness such as, for example, growth hormone-responsive dermatosis, dilated cardiomyopathy, eating disorders, reproductive disorders, and endocrine disorders.
  • Non-human albumin fusion proteins of the invention may also be used to promote healing of skin wounds, corneal injuries, bone fractures, and injuries of joints, tendons, or ligaments.
  • Non-human albumin fusion proteins of the invention may also be used to increase milk production in lactating animals, hi a preferred embodiment, the lactating animal is a dairy cow.
  • Non-human albumin fusion proteins of the invention may also be used to improve body condition in aged animals.
  • Non-human albumin fusion proteins of the invention may also be used to increase fertility, pregnancy rates, and reproductive success in domesticated animals.
  • Non-human albumin fusion proteins of the invention may also be used to improve the lean-to-fat ratio in animals raised for consumption, as well as to improve appetite, and increase body size and growth rate.
  • the present invention is further directed to fragments of the Therapeutic proteins described in Table 1, albumin proteins, and/or albumin fusion proteins of the invention.
  • the present invention is also directed to polynucleotides encoding fragments of the Therapeutic proteins described in Table 1, albumin proteins, and/or albumin fusion proteins of the invention.
  • Therapeutic protein portion of an albumin fusion protein of the invention include the full length protein as well as polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of the reference polypeptide (i.e., a Therapeutic protein referred to in Table 1, or a Therapeutic protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 2).
  • N- terminal deletions may be described by the general formula m to q, where q is a whole integer representing the total number of amino acid residues in a reference polypeptide (e.g., a
  • Therapeutic protein referred to in Table 1 or a Therapeutic protein portion of an albumin fusion protein of the invention, or a Therapeutic protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 2), and m is defined as any integer ranging from 2 to q minus 6. Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • fragments of serum albumin polypeptides corresponding to an albumin protein portion of an albumin fusion protein of the invention include the full length protein as well as polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of the reference polypeptide (i.e., serum albumin, or a serum albumin portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 2).
  • N-terminal deletions may be described by the general formula m to 585, where 585 is a whole integer representing the total number of amino acid residues in mature human serum albumin (SEQ ID NO: 1038), and m is defined as any integer ranging from 2 to 579.
  • Polynucleotides encoding these polypeptides are also encompassed by the invention, hi additional embodiments, N-terminal deletions may be described by the general formula m to 609, where 609 is a whole integer representing the total number of amino acid residues in full length human serum albumin (SEQ ID NO: 1094), and m is defined as any integer ranging from 2 to 603. Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • fragments of albumin fusion proteins of the invention include the full length albumin fusion protein as well as polypeptides having one or more residues deleted from the amino terminus of the albumin fusion protein (e.g., an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 2; or an albumin fusion protein having the amino acid sequence disclosed in column 6 of Table 2).
  • N-terminal deletions may be described by the general formula m to q, where q is a whole integer representing the total number of amino acid residues in the albumin fusion protein, and m is defined as any integer ranging from 2 to q minus 6.
  • Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • a reference polypeptide e.g., a Therapeutic protein; serum albumin protein; or albumin fusion protein of the invention
  • other functional activities e.g., biological activities, ability to multimerize, ability to bind a ligand
  • Therapeutic activities may still be retained.
  • the ability of polypeptides with C-terminal deletions to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptide generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the C-terminus. Whether a particular polypeptide lacking the N-terminal and/or C-terminal residues of a reference polypeptide retains
  • Therapeutic activity can readily be determined by routine methods described herein and/or otherwise known in the art.
  • the present invention further provides polypeptides having one or more residues deleted from the carboxy terminus of the amino acid sequence of a Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention (e.g., a Therapeutic protein referred to in Table 1, or a Therapeutic protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 2).
  • a Therapeutic protein referred to in Table 1 e.g., a Therapeutic protein referred to in Table 1, or a Therapeutic protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 2.
  • C-terminal deletions may be described by the general formula 1 to n, where n is any whole integer ranging from 6 to q minus 1, and where q is a whole integer representing the total number of amino acid residues in a reference polypeptide
  • a Therapeutic protein referred to in Table 1 e.g., a Therapeutic protein referred to in Table 1, or a Therapeutic protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in
  • the present invention provides polypeptides having one or more residues deleted from the carboxy terminus of the amino acid sequence of an albumin protein corresponding to an albumin protein portion of an albumin fusion protein of the invention
  • C-terminal deletions may be described by the general formula 1 to n, where n is any whole integer ranging from 6 to 584, where 584 is the whole integer representing the total number of amino acid residues in mature human serum albumin (SEQ ID NO: 1038) minus 1.
  • Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • C-terminal deletions may be described by the general formula 1 to n, where n is any whole integer ranging from 6 to 608, where 608 is the whole integer representing the total number of amino acid residues in serum albumin (SEQ ID NO: 1094) minus 1.
  • Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • the present invention provides polypeptides having one or more residues deleted from the carboxy terminus of an albumin fusion protein of the invention.
  • C-terminal deletions may be described by the general formula 1 to n, where n is any whole integer ranging from 6 to q minus 1, and where q is a whole integer representing the total number of amino acid residues in an albumin fusion protein of the invention.
  • Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • any of the above described N- or C-terminal deletions can be combined to produce a N- and C-terminal deleted reference polypeptide.
  • the invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini, which may be described generally as having residues m to n of a reference polypeptide (e.g., a Therapeutic protein referred to in Table 1, or a Therapeutic protein portion of an albumin fusion protein, of the invention, or a Therapeutic protein portion encoded by a polynucleotide or albumin fusion construct described in Table 2, or serum albumin (e.g., SEQ ID NO: 1038), or an albumin protein portion of an albumin fusion protein of the invention, or an albumin protein portion encoded by a polynucleotide or albumin fusion construct described in Table 2, or an albumin fusion protein, or an albumin fusion protein encoded by a polynucleotide or albumin fusion construct of the invention) where n and
  • the present application is also directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference polypeptide sequence (e.g., a Therapeutic protein referred to in Table 1, or a Therapeutic protein portion of an albumin fusion protein of the invention, or a Therapeutic protein portion encoded by a polynucleotide or albumin fusion construct described in Table 2, or serum albumin (e.g., SEQ
  • an albumin protein portion of an albumin fusion protein of the invention or an albumin protein portion encoded by a polynucleotide or albumin fusion construct described in Table 2, or an albumin fusion protein, or an albumin fusion protein encoded by a polynucleotide or albumin fusion construct of the invention) set forth herein, or fragments thereof.
  • the application is directed to proteins comprising polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to reference polypeptides having the amino acid sequence of N- and C-terminal deletions as described above. Polynucleotides encoding these polypeptides are also encompassed by the invention.
  • Prefe ⁇ ed polypeptide fragments of the invention are fragments comprising, or alternatively, consisting of, an amino acid sequence that displays a Therapeutic activity and/or functional activity (e.g. biological activity) of the polypeptide sequence of the Therapeutic protein or serum albumin protein of which the amino acid sequence is a fragment.
  • Other preferred polypeptide fragments are biologically active fragments.
  • Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention.
  • the biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.
  • Variant refers to a polynucleotide or nucleic acid differing from a reference nucleic acid or polypeptide, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the reference nucleic acid or polypeptide.
  • variant refers to a Therapeutic protein portion of an albumin fusion protein of the invention, albumin portion of an albumin fusion protein of the invention, or albumin fusion protein of the invention differing in sequence from a Therapeutic protein
  • variants are overall very similar, and, in many regions, identical to the amino acid sequence of the Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein, albumin protein corresponding to an albumin protein portion of an albumin fusion protein, and/or albumin fusion protein. Nucleic acids encoding these variants are also encompassed by the invention.
  • the present invention is also directed to proteins which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, the amino acid sequence of a Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention (e.g., the amino acid sequence of a Therapeutic proteimX disclosed in Table 1; or the amino acid sequence of a Therapeutic protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 1 and 2, or fragments or variants thereof), albumin proteins corresponding to an albumin protein portion of an albumin fusion protein of the invention (e.g., the amino acid sequence of an albumin protein portion of an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 1 and 2; the amino acid sequence shown in SEQ ID NO: 1038; or fragments or variants thereof), and/or albumin
  • polypeptides encompassed by the invention are polypeptides encoded by polynucleotides which hybridize to the complement of a nucleic acid molecule encoding an albumin fusion protein of the invention under stringent hybridization conditions (e.g., hybridization to filter bound DNA in
  • amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence.
  • the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence.
  • up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, or substituted with another amino acid.
  • These alterations of the reference sequence may occur at the amino- or carboxy-terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
  • an albumin fusion protein of the invention can be determined conventionally using known computer programs.
  • a preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al.
  • the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment.
  • This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score.
  • This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C- terminal residues of the subject sequence.
  • a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity.
  • the deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus.
  • the 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C- termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 residues were perfectly matched the final percent identity would be 90%.
  • a 90 residue subject sequence is compared with a 100 residue query sequence.
  • deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query.
  • percent identity calculated by FASTDB is not manually corrected.
  • residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
  • the variant will usually have at least 75 % (preferably at least about 80%,
  • sequence identity with a length of normal HA or Therapeutic protein which is the same length as the variant.
  • Homology or identity at the nucleotide or amino acid sequence level is determined by BLAST (Basic Local Alignment Search Tool) analysis using the algorithm employed by the programs blastp, blastn, blastx, tblastn and tblastx (Karlin et al, Proc. Natl. Acad. Sci. USA .87: 2264-2268 (1990) and Altschul, J. Mol. Evol. 36:
  • the approach used by the BLAST program is to first consider similar segments between a query sequence and a database sequence, then to evaluate the statistical significance of all matches that are identified and finally to summarize only those matches which satisfy a preselected threshold of significance.
  • the search parameters for histogram, descriptions, alignments, expect i.e., the statistical significance threshold for reporting matches against database sequences
  • cutoff matrix and filter are at the default settings.
  • the default scoring matrix used by blastp, blastx, tblastn, and tblastx is the BLOSUM62 matrix
  • the scoring matrix is set by the ratios of M (i.e., the reward score for a pair of matching residues) to N (i.e., the penalty score for mismatching residues), wherein the default values for M and N are 5 and -A, respectively.
  • M i.e., the reward score for a pair of matching residues
  • N i.e., the penalty score for mismatching residues
  • the polynucleotide variants of the invention may contain alterations in the coding regions, non-coding regions, or both. Especially prefe ⁇ ed are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred. Moreover, polypeptide variants in which less than 50, less than 40, less than 30, less than 20, less than
  • Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host, such as, yeast or E. coli).
  • a polynucleotide of the invention which encodes the albumin portion of an albumin fusion protein is optimized for expression in yeast or mammalian cells
  • a polynucleotide of the invention which encodes the Therapeutic protein portion of an albumin fusion protein is optimized for expression in yeast or mammalian cells.
  • a polynucleotide encoding an albumin fusion protein of the invention is optimized for expression in yeast or mammalian cells.
  • a codon optimized polynucleotide which encodes a Therapeutic protein portion of an albumin fusion protein does not hybridize to the wild type polynucleotide encoding the Therapeutic protein under stringent hybridization conditions as described herein.
  • a codon optimized polynucleotide which encodes an albumin portion of an albumin fusion protein does not hybridize to the wild type polynucleotide encoding the albumin protein under stringent hybridization conditions as described herein.
  • a codon optimized polynucleotide which encodes an albumin fusion protein does not hybridize to the wild type polynucleotide encoding the
  • Therapeutic protein portion or the albumin protein portion under stringent hybridization conditions as described herein.
  • a polynucleotide which encodes a Therapeutic protein portion of an albumin fusion protein does not comprise, or alternatively consist of, the naturally occurring sequence of that Therapeutic protein
  • a polynucleotide which encodes an albumin protein portion of an albumin fusion protein does not comprise, or alternatively consist of, the naturally occurring sequence of albumin protein.
  • a polynucleotide which encodes an albumin fusion protein does not comprise, or alternatively consist of, the naturally occurring sequence of a
  • Therapeutic protein portion or the albumin protein portion are provided.
  • Naturally occurring variants are called "allelic variants," and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism.
  • allelic variants can vary at either the polynucleotide and/or polypeptide level and are included in the present invention.
  • non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.
  • variants may be generated to improve or alter the characteristics of the polypeptides of the present invention.
  • one or more amino acids can be deleted from the N-terminus or C-terminus of the polypeptide of the present invention without substantial loss of biological function.
  • Ron et al. J. Biol. Chem. 268: 2984-
  • C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained.
  • other biological activities may still be retained.
  • the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus.
  • C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.
  • the invention further includes polypeptide variants which have a functional activity (e.g., biological activity and/or therapeutic activity), hi one embodiment, the invention provides variants of albumin fusion proteins that have a functional activity (e.g., biological activity and/or therapeutic activity) that corresponds to one or more biological and/or therapeutic activities of the Therapeutic protein co ⁇ esponding to the Therapeutic protein portion of the albumin fusion protein, another embodiment, the invention provides variants of albumin fusion proteins that have a functional activity (e.g., biological activity and/or therapeutic activity) that co ⁇ esponds to one or more biological and/or therapeutic activities of the Therapeutic protein co ⁇ esponding to the Therapeutic protein portion of the albumin fusion protein.
  • Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity. Polynucleotides encoding such variants are also encompassed by the invention.
  • the variants of the invention have conservative substitutions.
  • conservative substitutions is intended swaps within groups such as replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and He; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gin, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Tip, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
  • the first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.
  • the second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scamiing mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used. See Cunningham and Wells,
  • tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and He; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gin, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Tip, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
  • variants of the present invention include (i) polypeptides containing substitutions of one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) polypeptides containing substitutions of one or more of the amino acid residues having a substituent group, or (iii) polypeptides which have been fused with or chemically conjugated to another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), (iv) polypeptide containing additional amino acids, such as, for example, an IgG Fc fusion region peptide .
  • Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.
  • polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967); Robbins et al, Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier
  • the polypeptides of the invention comprise, or alternatively, consist of, fragments or variants of the amino acid sequence of an albumin fusion protein, the amino acid sequence of a Therapeutic protein and/or human serum albumin, wherein the fragments or variants have 1-5, 5-10, 5-25, 5-50, 10-50 or 50-150, amino acid residue additions, substitutions, and/or deletions when compared to the reference amino acid sequence.
  • the amino acid substitutions are conservative. Nucleic acids encoding these polypeptides are also encompassed by the invention.
  • the polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids.
  • the polypeptides may be modified by either natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini.
  • polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods.
  • Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer- RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
  • a polypeptide having functional activity refers to a polypeptide capable of displaying one or more known functional activities associated with the full-length, pro- protein, and/or mature form of a Therapeutic protein.
  • Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide for binding) to an anti-polypeptide antibody], immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide.
  • a polypeptide having biological activity refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a Therapeutic protein of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency, hi the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).
  • an albumin fusion protein of the invention has at least one biological and/or therapeutic activity associated with the Therapeutic protein portion
  • albumin fusion proteins of the invention can be assayed for functional activity (e.g., biological activity) using or routinely modifying assays known in the art, as well as assays described herein. Additionally, one of skill in the art may routinely assay fragments of a Therapeutic protein co ⁇ esponding to a Therapeutic protein portion of an albumin fusion protein, for activity using assays referenced in its co ⁇ esponding row of Table 1 (e.g., in column 3 of Table 1).
  • an albumin protein corresponding to an albumin protein portion of an albumin fusion protein, for activity using assays known in the art and/or as described in the Examples section below.
  • various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g.,
  • antibody binding is detected by detecting a label on the primary antibody
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody
  • the secondary antibody is labeled.
  • Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.
  • binding partner e.g., a receptor or a ligand
  • binding to that binding partner by an albumin fusion protein which comprises that Therapeutic protein as the Therapeutic protein portion of the fusion can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123 (1995).
  • the ability of physiological co ⁇ elates of an albumin fusion protein to bind to a substrate(s) of the Therapeutic polypeptide co ⁇ esponding to the Therapeutic protein portion of the fusion can be routinely assayed using techniques known in the art.
  • association with other components of the multimer can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non- reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., supra.
  • an albumin fusion protein comprising all or a portion of an antibody that binds a Therapeutic protein, has at least one biological and/or therapeutic activity (e.g., to specifically bind a polypeptide or epitope) associated with the antibody that binds a Therapeutic protein (or fragment or variant thereof) when it is not fused to albumin, h other prefe ⁇ ed embodiments, the biological activity and/or therapeutic activity of an albumin fusion protein comprising all or a portion of an antibody that binds a Therapeutic protein is the inhibition (i.e., antagonism) or activation (i.e., agonism) of one or more of the biological activities and/or therapeutic activities associated with the polypeptide that is specifically bound by antibody that binds a Therapeutic protein.
  • Albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be characterized in a variety of ways.
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for the ability to specifically bind to the same antigens specifically bound by the antibody that binds a Therapeutic protein co ⁇ esponding to the Therapeutic protein portion of the albumin fusion protein using techniques described herein or routinely modifying techniques known in the art.
  • albumin fusion proteins e.g., comprising at least a fragment or variant of an antibody that binds a Therapeutic protein
  • Assays for the ability of the albumin fusion proteins to (specifically) bind a specific protein or epitope may be performed in solution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria (e.g., U.S. Patent No. 5,223,409), on spores (e.g., Patent Nos.
  • Albumin fusion proteins comprising at least a fragment or variant of a Therapeutic antibody may also be assayed for their specificity and affinity for a specific protein or epitope using or routinely modifying techniques described herein or otherwise known in the art.
  • the albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for cross-reactivity with other antigens (e.g., molecules that have sequence/structure conservation with the molecule(s) specifically bound by the antibody that binds a Therapeutic protein (or fragment or variant thereof) corresponding to the Therapeutic protein portion of the albumin fusion protein of the invention) by any method known in the art.
  • Immunoassays which can be used to analyze (immunospecific) binding and cross-reactivity include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few.
  • Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Cu ⁇ ent Protocols in Molecular Biology, Vol. 1, John
  • Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIP A buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate,
  • albumin fusion protein of the invention e.g., comprising at least a fragment or variant of an antibody that binds a Therapeutic protein
  • adding sepharose beads coupled to an anti-albumin antibody for example, to the cell lysate, incubating for about an hour or more at 40 degrees C, washing the beads in lysis buffer and resuspending the beads in
  • the ability of the albumin fusion protein to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis.
  • One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the albumin fusion protein to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads).
  • immunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994, Cu ⁇ ent Protocols in Molecular Biology, Vol. 1, John
  • Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%- 20% SDS-PAGE depending on the molecular weight of the antigen), transfe ⁇ ing the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), applying the albumin fusion protein of the invention (diluted in blocking buffer) to the membrane, washing the membrane in washing buffer, applying a secondary antibody (which recognizes the albumin fusion protein, e.g., an anti-human serum albumin antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32 P or
  • an enzymatic substrate e.g., horseradish peroxida
  • ELISAs comprise preparing antigen, coating the well of a 96-well microtiter plate with the antigen, washing away antigen that did not bind the wells, adding the albumin fusion protein (e.g., comprising at least a fragment or variant of an antibody that binds a
  • Therapeutic protein of the invention conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, washing away unbound or non-specifically bound albumin fusion proteins, and detecting the presence of the albumin fusion proteins specifically bound to the antigen coating the well, hi ELISAs the albumin fusion protein does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes albumin fusion protein) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, the albumin fusion protein may be coated to the well.
  • an enzymatic substrate e.g., horseradish peroxidase or alkaline phosphatase
  • the detectable molecule could be the antigen conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase).
  • an enzymatic substrate e.g., horseradish peroxidase or alkaline phosphatase.
  • ELISAs see, e.g., Ausubel et al, eds, 1994, Cu ⁇ ent
  • the binding affinity of an albumin fusion protein to a protein, antigen, or epitope and the off-rate of an albumin fusion protein-protein/antigen/epitope interaction can be determined by competitive binding assays.
  • a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., 3 H or 125 I) with the albumin fusion protein of the invention in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen.
  • labeled antigen e.g., 3 H or 125 I
  • the affinity of the albumin fusion protein for a specific protein, antigen, or epitope and the binding off-rates can be determined from the data by Scatchard plot analysis.
  • Competition with a second protein that binds the same protein, antigen or epitope as the albumin fusion protein can also be determined using radioimmunoassays.
  • the protein, antigen or epitope is incubated with an albumin fusion protein conjugated to a labeled compound (e.g., H or I) in the presence of increasing amounts of an unlabeled second protein that binds the same protein, antigen, or epitope as the albumin fusion protein of the invention.
  • a labeled compound e.g., H or I
  • BIAcore kinetic analysis is used to determine the binding on and off rates of albumin fusion proteins of the invention to a protein, antigen or epitope.
  • BIAcore kinetic analysis comprises analyzing the binding and dissociation of albumin fusion proteins, or specific polypeptides, antigens or epitopes from chips with immobilized specific polypeptides, antigens or epitopes or albumin fusion proteins, respectively, on their surface.
  • Antibodies that bind a Therapeutic protein corresponding to the Therapeutic protein portion of an albumin fiision protein may also be described or specified in terms of their binding affinity for a given protein or antigen, preferably the antigen which they specifically bind.
  • Prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 "2 M, 10 "2 M, 5 X 10 "3 M, 10 "3 M, 5 X 10 "4 M, 10 "4 M. More prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 "5 M, 10 "5 M, 5 X
  • prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 " M, 10 "9 M, 5 X
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, has an affinity for a given protein or epitope similar to that of the co ⁇ esponding antibody (not fused to albumin) that binds a Therapeutic protein, taking into account the valency of the albumin fusion protein (comprising at least a fragment or variant of an antibody that binds a
  • Therapeutic protein and the valency of the co ⁇ esponding antibody.
  • assays described herein may routinely be applied to measure the ability of albumin fusion proteins and fragments, variants and derivatives thereof to elicit biological activity and/or Therapeutic activity (either in vitro or in vivo) related to either the Therapeutic protein portion and/or albumin portion of the albumin fusion protein.
  • Other methods will be known to the skilled artisan and are within the scope of the invention.
  • an albumin fiision protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion.
  • An additional embodiment comprises at least a fragment or variant of a
  • HSA human serum albumin
  • HA human albumin
  • albumin and HA are broader, and encompass human serum albumin (and fragments and variants thereof) as well as albumin from other species (and fragments and variants thereof).
  • albumin refers collectively to albumin protein or amino acid sequence, or an albumin fragment or variant, having one or more functional activities (e.g., biological activities) of albumin.
  • albumin refers to human albumin or fragments thereof (see for example, EP 201 239, EP 322 094 WO 97/24445, WO95/23857) especially the mature form of human albumin as shown in Figure 1 and SEQ ID NO: 1038, or albumin from other vertebrates or fragments thereof, or analogs or variants of these molecules or fragments thereof.
  • the human serum albumin protein used in the albumin fusion proteins of the invention contains one or both of the following sets of point mutations with reference to SEQ ID NO: 1038: Leu-407 to Ala, Leu-408 to Val, Val-409 to
  • albumin fusion proteins of the invention that contain one or both of above-described sets of point mutations have improved stability/resistance to yeast Yap3p proteolytic cleavage, allowing increased production of recombinant albumin fusion proteins expressed in yeast host cells.
  • a portion of albumin sufficient to prolong the therapeutic activity or shelf-life of the Therapeutic protein refers to a portion of albumin sufficient in length or structure to stabilize or prolong the therapeutic activity of the protein so that the shelf life of the Therapeutic protein portion of the albumin fusion protein is prolonged or extended compared to the shelf-life in the non-fusion state.
  • the albumin portion of the albumin fusion proteins may comprise the full length of the HA sequence as described above, or may include one or more fragments thereof that are capable of stabilizing or prolonging the therapeutic activity. Such fragments may be of 10 or more amino acids in length or may include about 15, 20, 25, 30, 50, or more contiguous amino acids from the HA sequence or may include part or all of specific domains of HA. For instance, one or more fragments of
  • HA spanning the first two immunoglobulin-like domains may be used.
  • the HA fragment is the mature form of HA.
  • the albumin portion of the albumin fusion proteins of the invention may be a variant of normal HA.
  • the Therapeutic protein portion of the albumin fusion proteins of the invention may also be variants of the Therapeutic proteins as described herein.
  • variants includes insertions, deletions and substitutions, either conservative or non conservative, where such changes do not substantially alter one or more of the oncotic, useful ligand-binding and non-immunogenic properties of albumin, or the active site, or active domain which confers the therapeutic activities of the Therapeutic proteins.
  • albumin fusion proteins of the invention may include naturally occurring polymorphic variants of human albumin and fragments of human albumin, for example those fragments disclosed in EP 322 094 (namely HA (Pn), where n is
  • the albumin may be derived from any vertebrate, especially any mammal, for example human, cow, sheep, or pig. Non-mammalian albumins include, but are not limited to, hen and salmon.
  • the albumin portion of the albumin fusion protein may be from a different animal than the Therapeutic protein portion.
  • an HA fragment or variant will be at least 100 amino acids long, preferably at least 150 amino acids long.
  • the HA variant may consist of or alternatively comprise at least one whole domain of HA, for example domains 1 (amino acids
  • Each domain is itself made up of two homologous subdomains namely 1-105, 120-194, 195-291, 316-387, 388-491 and 512-585, with flexible inter-subdomain linker regions comprising residues LyslO ⁇ to Glul 19, Glu292 to Val315 and Glu492 to Ala511.
  • the albumin portion of an albumin fusion protein of the invention comprises at least one subdomain or domain of HA or conservative modifications thereof. If the fusion is based on subdomains, some or all of the adjacent linker is preferably used to link to the Therapeutic protein moiety.
  • Antibodies that Specifically bind Therapeutic proteins are also Therapeutic proteins [0156]
  • the present invention also encompasses albumin fusion proteins that comprise at least a fragment or variant of an antibody that specifically binds a Therapeutic protein disclosed in Table 1. It is specifically contemplated that the term "Therapeutic protein” encompasses antibodies that bind a Therapeutic protein (e.g., as Described in column I of Table 1) and fragments and variants thereof.
  • an albumin fusion protein of the invention may contain at least a fragment or variant of a Therapeutic protein, and/or at least a fragment or variant of an antibody that binds a Therapeutic protein.
  • the basic antibody structural unit is known to comprise a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one
  • each chain includes a variable region f about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function.
  • Human light chains are classified as kappa and lambda light chains.
  • Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. See generally, Fundamental Immunology Chapters 3-5 (Paul, W., ed., 4th ed. Raven Press, N.Y.
  • variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact IgG antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are the same.
  • the chains all exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs.
  • the CDR regions in general, are the portions of the antibody which make contact with the antigen and determine its specificity.
  • the CDRs from the heavy and the light chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chains variable regions comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • variable regions are connected to the heavy or light chain constant region.
  • the assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989).
  • antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen (e.g., a molecule containing one or more CDR regions of an antibody).
  • Antibodies that may correspond to a Therapeutic protein portion of an albumin fusion protein include, but are not limited to, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies (e.g., single chain Fvs), Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies specific to antibodies of the invention), and epitope-binding fragments of any of the above (e.g., VH domains, VL domains, or one or more CDR regions).
  • single chain antibodies e.g., single chain Fvs
  • Fab fragments fragments
  • F(ab') fragments fragments produced by a Fab expression library
  • anti-idiotypic antibodies including, e.g., anti-Id antibodies specific to antibodies of the invention
  • epitope-binding fragments of any of the above e.g., VH domains, V
  • the present invention encompasses albumin fusion proteins that comprise at least a fragment or variant of an antibody that binds a Therapeutic Protein (e.g., as disclosed in Table 1) or fragment or variant thereof.
  • Antibodies that bind a Therapeutic protein may be from any animal origin, including birds and mammals.
  • the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken antibodies.
  • the antibodies are human antibodies.
  • human antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries and xenomice or other organisms that have been genetically engineered to produce human antibodies.
  • the antibody molecules that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • the antibody molecules that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein are IgGl.
  • the immunoglobulin molecules that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein are IgG2. In other prefe ⁇ ed embodiments, the immunoglobulin molecules that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein are IgG4.
  • the antibodies that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein are human antigen- binding antibody fragments of the present invention and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain.
  • Antigen-binding antibody fragments, including single-chain antibodies may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CHI, CH2, and CH3 domains.
  • Therapeutic protein portion of an albumin fusion protein may be monospecific, bispecific, trispecific or of greater multispecificity.
  • Multispecific antibodies may be specific for different epitopes of a Therapeutic protein or may be specific for both a Therapeutic protein as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Patent Nos.
  • Antibodies that bind a Therapeutic protein may be bispecific or bifunctional which means that the antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites.
  • Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann Clin. Exp.
  • bispecific antibodies may be formed as "diabodies” (Holliger et al. "'Diabodies': small bivalent and bispecific antibody fragments” PNAS USA 90:6444-6448 (1993)) or "Janusins"
  • the present invention also provides albumin fusion proteins that comprise, fragments or variants (including derivatives) of an antibody described herein or known elsewhere in the art. Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a molecule of the invention, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis which result in amino acid substitutions.
  • the variants encode less than 50 amino acid substitutions, less than 40 amino acid substitutions, less than 30 amino acid substitutions, less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the reference VH domain,
  • the variants encode substitutions of VHCDR3.
  • the variants have conservative amino acid substitutions at one or more predicted non-essential amino acid residues.
  • Therapeutic protein portion of an albumin fusion protein may be described or specified in terms of the epitope(s) or portion(s) of a Therapeutic protein which they recognize or specifically bind.
  • Antibodies which specifically bind a Therapeutic protein or a specific epitope of a Therapeutic protein may also be excluded. Therefore, the present invention encompasses antibodies that specifically bind Therapeutic proteins, and allows for the exclusion of the same.
  • albumin fiision proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, binds the same epitopes as the unfused fragment or variant of that antibody itself.
  • Therapeutic protein portion of an albumin fusion protein may also be described or specified in terms of their cross-reactivity.
  • Antibodies that do not bind any other analog, ortholog, or homolog of a Therapeutic protein are included.
  • Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% sequence identity (as calculated using methods known in the art and described herein) to a Therapeutic protein are also included in the present invention.
  • Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% sequence identity (as calculated using methods known in the art and described herein) to a Therapeutic protein are also included in the present invention.
  • the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein.
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, has similar or substantially identical cross reactivity characteristics compared to the fragment or variant of that particular antibody itself.
  • Antibodies that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein of the invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention.
  • Prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 " M, 10 " M, 5 X 10 "3 M, 10 "3 M, 5 X 10 "4 M, 10 "4 M.
  • More prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 "5 M, 10 "5 M, 5 X 10 "6 M, i ⁇ *M, 5 X 10 "7 M, 10 7 M, 5 X 10 "8 M or 10 "8 M.
  • Even more prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 "9 M, 10 "9 M, 5 X 10 "10 M, 10 “10 M, 5 X 10 "n M, 10 “n M, 5 X 10 "12 M, l0”12 M, 5 X 10 "13 M, 10 "13 M, 5 X 10 "14 M, 10 "14 M, 5 X 10 "15 M, or 10 " 15 M.
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, has an affinity for a given protein or epitope similar to that of the co ⁇ esponding antibody (not fused to albumin) that binds a Therapeutic protein, taking into account the valency of the albumin fusion protein (comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) and the valency of the co ⁇ esponding antibody.
  • the invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of a Therapeutic protein as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein.
  • the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85 %, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, competitively inhibits binding of a second antibody to an epitope of a Therapeutic protein.
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, competitively inhibits binding of a second antibody to an epitope of a Therapeutic protein by at least 95%, at least 90%, at least 85 %, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.
  • Therapeutic protein portion of an albumin fusion protein of the invention may act as agonists or antagonists of the Therapeutic protein.
  • the present invention includes antibodies which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully.
  • the invention features both receptor-specific antibodies and ligand-specific antibodies.
  • the invention also features receptor-specific antibodies which do not prevent ligand binding but prevent receptor activation.
  • Receptor activation i.e., signaling
  • receptor activation may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by western blot analysis (for example, as described supra).
  • antibodies are provided that inhibit ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody.
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, has similar or substantially similar characteristics with regard to preventing ligand binding and/or preventing receptor activation compared to an un-fused fragment or variant of the antibody that binds the Therapeutic protein.
  • the invention also features receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand.
  • receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand.
  • neutralizing antibodies which bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies which bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor.
  • Further included in the invention are antibodies which activate the receptor. These antibodies may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing dimerization of the receptor.
  • the antibodies may be specified as agonists, antagonists or inverse agonists for
  • Therapeutic proteins e.g. as disclosed in Table 1.
  • the above antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Patent No.
  • Therapeutic protein have similar or substantially identical agonist or antagonist properties as an un-fused fragment or variant of the antibody that binds the Therapeutic protein.
  • Therapeutic protein portion of an albumin fusion protein of the invention may be used, for example, to purify, detect, and target Therapeutic proteins, including both in in vitro and in vivo diagnostic and therapeutic methods.
  • the antibodies have utility in immunoassays for qualitatively and quantitatively measuring levels of the Therapeutic protein in biological samples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold
  • albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, may be used, for example, to purify, detect, and target Therapeutic proteins, including both in vitro and in vivo diagnostic and therapeutic methods.
  • Therapeutic protein portion of an albumin fusion protein include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the antibody.
  • the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids. Albumin fusion proteins of the invention may also be modified as described above.
  • Therapeutic protein portion of an albumin fusion protein of the invention may be generated by any suitable method known in the art.
  • Polyclonal antibodies to an antigen-of-interest can be produced by various procedures well known in the art.
  • a Therapeutic protein may be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the antigen.
  • adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art.
  • Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof.
  • monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in
  • the term "monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology.
  • the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
  • mice can be immunized with a Therapeutic protein or fragment or variant thereof, an albumin fusion protein, or a cell expressing such a Therapeutic protein or fragment or variant thereof or albumin fusion protein.
  • an immune response e.g., antibodies specific for the antigen are detected in the mouse serum
  • the mouse spleen is harvested and splenocytes isolated.
  • the splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution.
  • hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention.
  • Ascites fluid which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.
  • the present invention provides methods of generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with an antigen of the invention with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind a polypeptide of the invention.
  • EBV Epstein Ban Virus
  • Protocols for generating EBV-transformed B cell lines are commonly known in the art, such as, for example, the protocol outlined in Chapter 7.22 of Cu ⁇ ent Protocols in Immunology, Coligan et al., Eds., 1994, John Wiley & Sons, NY, which is hereby incorporated in its entirety by reference.
  • the source of B cells for transformation is commonly human peripheral blood, but
  • B cells for transformation may also be derived from other sources including, but not limited to, lymph nodes, tonsil, spleen, tumor tissue, and infected tissues. Tissues are generally made into single cell suspensions prior to EBV transformation. Additionally, steps may be taken to either physically remove or inactivate T cells (e.g., by treatment with cyclosporin A) in B cell-containing samples, because T cells from individuals seropositive for anti-EBV antibodies can suppress B cell immortalization by EBV.
  • Tissues are generally made into single cell suspensions prior to EBV transformation. Additionally, steps may be taken to either physically remove or inactivate T cells (e.g., by treatment with cyclosporin A) in B cell-containing samples, because T cells from individuals seropositive for anti-EBV antibodies can suppress B cell immortalization by EBV.
  • the sample containing human B cells is innoculated with EBV, and cultured for 3-4 weeks.
  • a typical source of EBV is the culture supernatant of the B95-8 cell line (ATCC #VR-1492).
  • Physical signs of EBV transformation can generally be seen towards the end of the 3-4 week culture period.
  • phase-contrast microscopy transformed cells may appear large, clear, hairy and tend to aggregate in tight clusters of cells.
  • EBV lines are generally polyclonal. However, over prolonged periods of cell cultures, EBV lines may become monoclonal or polyclonal as a result of the selective outgrowth of particular B cell clones. Alternatively, polyclonal EBV transformed lines may be subcloned
  • Suitable fusion partners for EBV transformed cell lines include mouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma cell lines
  • human x mouse e.g, SPAM-8, SBC-H20, and CB-F7
  • human cell lines e.g., GM 1500
  • the present invention also provides a method of generating polyclonal or monoclonal human antibodies against polypeptides of the invention or fragments thereof, comprising EBV-transformation of human B cells.
  • Antibody fragments which recognize specific epitopes may be generated by known techniques.
  • Fab and F(ab')2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments).
  • F(ab')2 fragments contain the variable region, the light chain constant region and the CHI domain of the heavy chain.
  • antibodies that bind to a Therapeutic protein can also be generated using various phage display methods known in the art.
  • phage display methods functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them.
  • phage can be utilized to display antigen binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine).
  • Phage expressing an antigen binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead.
  • Phage used in these methods are typically filamentous phage including fd and Ml 3 binding domains expressed from phage with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene IH or gene VIE protein.
  • phage display methods that can be used to make antibodies that bind to a Therapeutic protein include those disclosed in Brinkman et al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol.
  • the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described in detail below.
  • a chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.
  • Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al.,
  • Humanized antibodies are antibody molecules from non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non- human species and a framework regions from a human immunoglobulin molecule.
  • CDRs complementarity determining regions
  • framework residues in the human framework regions will be substituted with the co ⁇ esponding residue from the CDR donor antibody to alter, preferably improve, antigen binding.
  • framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Patent No.
  • Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO
  • Human antibodies are particularly desirable for therapeutic treatment of human patients.
  • Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Patent Nos. 4,444,887 and
  • Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes.
  • the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells.
  • the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes.
  • the mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production.
  • the modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice.
  • the chimeric mice are then bred to produce homozygous offspring which express human antibodies.
  • the transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention.
  • Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology.
  • the human immunoglobulin transgenes harbored by the transgenic mice rea ⁇ ange during B cell differentiation, and subsequently undergo class switching and somatic mutation.
  • Completely human antibodies which recognize a selected epitope can be generated using a technique refe ⁇ ed to as "guided selection.”
  • a selected non-human monoclonal antibody e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., Bio/technology 12:899-903 (1988)).
  • the invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody and fragments thereof.
  • the invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a Therapeutic protein, and more preferably, an antibody that binds to a polypeptide having the amino acid sequence of a "Therapeutic protein:X" as disclosed in the "SEQ ID NO:Z" column of Table 2.
  • the polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al.,
  • a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody) by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by a suitable source (e.g.,
  • PCR may then be cloned into replicable cloning vectors using any method well known in the art (See Example 107).
  • nucleotide sequence and co ⁇ esponding amino acid sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d
  • the amino acid sequence of the heavy and/or light chain variable domains may be inspected to identify the sequences of the complementarity determining regions (CDRs) by methods that are well know in the art, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability.
  • CDRs complementarity determining regions
  • one or more of the CDRs may be inserted within framework regions, e.g., into human framework regions to humanize a non-human antibody, as described supra.
  • the framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, e.g., Chothia et al., J. Mol. Biol.
  • the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds a polypeptide of the invention.
  • one or more amino acid substitutions may be made within the framework regions, and, preferably, the amino acid substitutions improve binding of the antibody to its antigen. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds.
  • Other alterations to the polynucleotide are encompassed by the present invention and within the skill of the art.
  • a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region, e.g., humanized antibodies.
  • Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.
  • Techniques for the assembly of functional Fv fragments in E. coli may also be used (Ske ⁇ a et al., Science 242:1038- 1041 (1988)).
  • an antibody, or fragment, derivative or analog thereof e.g., a heavy or light chain of an antibody or a single chain antibody
  • an expression vector containing a polynucleotide that encodes the antibody Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art.
  • a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein.
  • Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination.
  • the invention thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter.
  • Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and
  • variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.
  • the expression vector is transfe ⁇ ed to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody.
  • the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody, operably linked to a heterologous promoter.
  • vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.
  • host-expression vector systems may be utilized to express the antibody molecules of the invention.
  • Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ.
  • These include but are not limited to microorganisms such as bacteria (e.g., E. coli, B.
  • subtilis transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors contaimng antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from
  • bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule.
  • mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).
  • a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable.
  • vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., EMBO J.
  • pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST).
  • fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione.
  • the pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
  • AcNPV is used as a vector to express foreign genes.
  • the virus grows in Spodoptera frugiperda cells.
  • the antibody coding sequence may be cloned individually into non- essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).
  • an adenovirus In mammalian host cells, a number of viral-based expression systems may be utilized.
  • the antibody coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence.
  • This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non- essential region of the viral genome (e.g., region El or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts, (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)).
  • Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert.
  • exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic.
  • the efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., Methods in Enzymol. 153:51-544 (1987)).
  • a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein.
  • Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products.
  • Appropriate cell lines or host systems can be chosen to ensure the co ⁇ ect modification and processing of the foreign protein expressed.
  • eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.
  • mammalian host cells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.
  • stable expression is prefe ⁇ ed.
  • cell lines which stably express the antibody molecule may be engineered.
  • host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker.
  • appropriate expression control elements e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.
  • engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media.
  • the selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines.
  • This method may advantageously be used to engineer cell lines which express the antibody molecule.
  • Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the antibody molecule.
  • a number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine- guanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA
  • dhfr which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al.,
  • the expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol.3.
  • Glutaminase GS
  • DHFR DHFR
  • An advantage of glutamine synthase based vectors are the availability of cell lines (e.g., the murine myeloma cell fine, NS0) which are glutamine synthase negative.
  • Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g. Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene.
  • a glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462;
  • glutamine synthase expression vectors that may be used according to the present invention are commercially available from suppliers, including, for example Lonza Biologies, Inc. (Portsmouth, NH). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al, Bio/technology 10:169(1992) and in Biblia and Robinson Biotechnol.
  • the host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide.
  • the two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides.
  • a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986);
  • the coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.
  • an antibody molecule of the invention may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography
  • the antibodies that bind to a Therapeutic protein and that may co ⁇ espond to a Therapeutic protein portion of an albumin fusion protein of the invention or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.
  • Antibodies that bind a Therapeutic protein or fragments or variants can be fused to marker sequences, such as a peptide to facilitate purification.
  • the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available.
  • hexa-histidine provides for convenient purification of the fusion protein.
  • peptide tags useful for purification include, but are not limited to, the hemagglutinin tag (also called the "HA tag”), which co ⁇ esponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the "flag" tag.
  • HA tag also called the "HA tag”
  • the present invention further encompasses antibodies or fragments thereof conjugated to a diagnostic or therapeutic agent.
  • the antibodies can be used diagnostically to, for example, monitor the development or progression of a tumor as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions.
  • the detectable substance may be coupled or conjugated either directly to the antibody (or fragment thereof) or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Patent No. 4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics according to the present invention.
  • suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;
  • suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin;
  • suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin;
  • an example of a luminescent material includes luminol;
  • examples of bioluminescent materials include luciferase, luciferin, and aequorin;
  • suitable radioactive material include 1251, 1311, l l lln or 99Tc. Other examples of detectable substances have been described elsewhere herein.
  • an antibody of the invention may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213B
  • a cytotoxin or cytotoxic agent includes any agent that is detrimental to cells.
  • Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mit ⁇ xantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.
  • Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6- mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, sfreptozotocin, mitomycin C, and cis- dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e
  • the conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents.
  • the drug moiety may be a protein or polypeptide possessing a desired biological activity.
  • Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, alpha-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO 97/33899), AIM ⁇ (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al, Int.
  • a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin
  • a protein such as tumor necrosis factor, alpha-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an
  • VEGI vascular endothelial growth factor
  • a thrombotic agent or an anti- angiogenic agent e.g., angiostatin or endostatin
  • biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • IL-1 interleukin-1
  • IL-2 interleukin-2
  • IL-6 interleukin-6
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen.
  • solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
  • an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No. 4,676,980, which is incorporated hergin by reference in its entirety.
  • An antibody, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.
  • Therapeutic protein portion of an albumin fusion protein of the invention include, but are not limited to, antibodies that bind a Therapeutic protein disclosed in the "Therapeutic Protein X" column of Table 1, or a fragment or variant thereof.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH domain.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, one, two or three VH CDRs.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH CDR1.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH CDR2. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH CDR3.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL domain.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, one, two or three VL CDRs.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL CDR1.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL CDR2.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL CDR3.
  • the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, one, two, three, four, five, or six VH and/or VL CDRs.
  • the fragment or variant of an antibody that immunospecifically binds a Therapeutic protein and that co ⁇ esponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, an scFv comprising the VH domain of the Therapeutic antibody, linked to the VL domain of the therapeutic antibody by a peptide linker such as (Gly 4 Ser) 3 (SEQ ID NO: 1092).
  • the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) may be utilized for immunophenotyping of cell lines and biological samples.
  • Therapeutic proteins of the present invention may be useful as cell- specific markers, or more specifically as cellular markers that are differentially expressed at various stages of differentiation and/or maturation of particular cell types.
  • Monoclonal antibodies (or albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker.
  • Various techniques can be utilized using monoclonal antibodies (or albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, "panning" with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Patent 5,985,660; and Morrison et al, Cell, 95:737-49 (1999)). .
  • the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) may be characterized in a variety of ways.
  • Albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for the ability to specifically bind to the same antigens specifically bound by the antibody that binds a Therapeutic protein co ⁇ esponding to the antibody that binds a Therapeutic protein portion of the albumin fusion protein using techniques described herein or routinely modifying techniques known in the art.
  • Assays for the ability of the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) to (specifically) bind a specific protein or epitope may be performed in solution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria (e.g., U.S. Patent No. 5,223,409), on spores (e.g., Patent Nos.
  • the antibodies of the invention or albumin, fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) may also be assayed for their specificity and affinity for a specific protein or epitope using or routinely modifying techniques described herein or otherwise known in the art.
  • the albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for cross-reactivity with other antigens (e.g., molecules that have sequence/structure conservation with the molecule(s) specifically bound by the antibody that binds a Therapeutic protein (or fragment or variant thereof) co ⁇ esponding to the Therapeutic protein portion of the albumin fusion protein of the invention) by any method known in the art.
  • antigens e.g., molecules that have sequence/structure conservation with the molecule(s) specifically bound by the antibody that binds a Therapeutic protein (or fragment or variant thereof) co ⁇ esponding to the Therapeutic protein portion of the albumin fusion protein of the invention
  • Immunoassays which can be used to analyze (immunospecific) binding and cross-reactivity include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoprecipitation assays, precipitm reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few.
  • Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Cu ⁇ ent Protocols in Molecular Biology, Vol. 1, John
  • Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RDPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate,
  • the ability of the antibody or albumin fusion protein of the invention to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis.
  • One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody or albumin fusion protein to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads).
  • background e.g., pre-clearing the cell lysate with sepharose beads.
  • Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%- 20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), applying the antibody or albumin fusion protein of the invention (diluted in blocking buffer) to the membrane, washing the membrane in washing buffer, applying a secondary antibody (which recognizes the albumin fusion protein, e.g., an anti-human serum albumin antibody) conjugated to an enzymatic substrate
  • a polyacrylamide gel e.g., 8%- 20% SDS-PAGE depending on the molecular weight of the antigen
  • a membrane such as nitrocellulose, PVDF or nylon
  • blocking solution e.g.,
  • ELISAs comprise preparing antigen, coating the well of a 96-well microtiter plate with the antigen, washing away antigen that did not bind the wells, adding the antibody or albumin fusion protein (comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) of the invention conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, washing away unbound or non-specifically bound albumin fusion proteins, and detecting the presence of the antibody or albumin fusion proteins specifically bound to the antigen coating the well.
  • an enzymatic substrate e.g., horseradish peroxidase or alkaline phosphatase
  • the antibody or albumin fusion protein does not have to be conjugated to a detectable compound; instead, a second antibody
  • the detectable molecule could be the antigen conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase).
  • an enzymatic substrate e.g., horseradish peroxidase or alkaline phosphatase.
  • the binding affinity of an albumin fusion protein to a protein, antigen, or epitope and the off-rate of an antibody- or albumin fusion protein-protein/antigen/epitope interaction can be determined by competitive binding assays.
  • a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., H or
  • the affinity of the antibody or albumin fusion protein of the invention for a specific protein, antigen, or epitope and the binding off-rates can be determined from the data by Scatchard plot analysis. Competition with a second protein that binds the same protein, antigen or epitope as the antibody or albumin fusion protein, can also be determined using radioimmunoassays.
  • the protein, antigen or epitope is incubated with an antibody or albumin fusion protein of the invention conjugated to a labeled compound (e.g., 3 H or 125 I) in the presence of increasing amounts of an unlabeled second protein that binds the same protein, antigen, or epitope as the albumin fusion protein of the invention.
  • a labeled compound e.g., 3 H or 125 I
  • BIAcore kinetic analysis is used to determine the binding on and off rates of antibody or albumin fusion proteins of the invention to a protein, antigen or epitope.
  • BIAcore kinetic analysis comprises analyzing the binding and dissociation of antibodies, albumin fusion proteins, or specific polypeptides, antigens or epitopes from chips with immobilized specific polypeptides, antigens or epitopes, antibodies or albumin fusion proteins, respectively, on their surface.
  • the present invention is further directed to antibody-based therapies which involve administering antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the disclosed diseases, disorders, or conditions.
  • Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (including fragments, analogs and derivatives thereof as described herein), nucleic acids encoding antibodies of the invention
  • albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, and nucleic acids encoding such albumin fusion proteins.
  • the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein can be used to treat, inhibit or prevent diseases, disorders or conditions associated with abe ⁇ ant expression and/or activity of a Therapeutic protein, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein.
  • the treatment and/or prevention of diseases, disorders, or conditions associated with abe ⁇ ant expression and/or activity of a Therapeutic protein includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions, antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.
  • the present invention is directed to antibody-based therapies which involve administering antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein to an animal, preferably a mammal, and most preferably a human, patient for treating one or more diseases, disorders, or conditions, including but not limited to: neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions., and/or as described elsewhere herein.
  • Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (e.g., antibodies directed to the full length protein expressed on the cell surface of a mammalian cell; antibodies directed to an epitope of a Therapeutic protein and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein).
  • the antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with abe ⁇ ant expression and/or activity of a Therapeutic protein, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein.
  • the treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a Therapeutic protein includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions.
  • Antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.
  • a summary of the ways in which the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be used therapeutically includes binding Therapeutic proteins locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below.
  • CDC complement
  • ADCC effector cells
  • the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as, e.g., EL-2, IL-3 and IL-7), for example, which serve to increase the number or activity of effector cells which interact with the antibodies.
  • lymphokines or hematopoietic growth factors such as, e.g., EL-2, IL-3 and IL-7
  • the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be administered alone or in combination with other types of treatments (e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents).
  • treatments e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents.
  • administration of products of a species origin or species reactivity in the case of antibodies
  • human antibodies, fragments derivatives, analogs, or nucleic acids are administered to a human patient for therapy or prophylaxis.
  • Prefe ⁇ ed binding affinities include dissociation constants or Kd's less than 5 X 10 "2 M, 10 "2 M, 5 X 10 "3 M, 10 “3 M, 5 X 10 "4 M, 10 "4 M. More prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 "5 M, 10 "5 M, 5 X 10 "6 M, 10 " ⁇ , 5 X 10 "7 M, 10 7 M, 5 X 10 "8 M or 10 "8 M.
  • Even more prefe ⁇ ed binding affinities include those with a dissociation constant or Kd less than 5 X 10 "9 M, 10 “9 M, 5 X 10 "10 M, 10 “10 M, 5 X 10 “ “ M, 10 “u M, 5 X 10 "12 M, 10 “12 M, 5 X 10 "13 M, 10 “13 M, 5 X 10 "14 M, 10 “14 M, 5 X 10 "15 M, or 10 " 15 M.
  • nucleic acids comprising sequences encoding antibodies that bind therapeutic proteins or albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein are administered to treat, inhibit or prevent a disease or disorder associated with abe ⁇ ant expression and/or activity of a Therapeutic protein, by way of gene therapy.
  • Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid.
  • the nucleic acids produce their encoded protein that mediates a therapeutic effect.
  • the compounds or pharmaceutical compositions of the invention are preferably tested in vitro, and then in vivo for the desired therapeutic or prophylactic activity, prior to use in humans.
  • in vitro assays to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include, the effect of a compound on a cell line or a patient tissue sample.
  • the effect of the compound or composition on the cell line and/or tissue sample can be determined utilizing techniques known to those of skill in the art including, but not limited to, rosette formation assays and cell lysis assays.
  • in vitro assays which can be used to determine whether administration of a specific compound is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a compound, and the effect of such compound upon the tissue sample is observed.
  • the invention provides methods of treatment, inhibition and prophylaxis by administration to a subject of an effective amount of a compound or pharmaceutical composition of the invention.
  • the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects).
  • the subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.
  • Formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin are described above; additional appropriate formulations and routes of administration can be selected from among those described herein below.
  • Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc.
  • Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
  • Ommaya reservoir Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
  • a protein, including an antibody, of the invention care must be taken to use materials to which the protein does not absorb.
  • the compound or composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in
  • the compound or composition can be delivered in a controlled release system.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980);
  • polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise
  • a controlled release system can be placed in proximity of the therapeutic target, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see
  • nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.
  • compositions comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water is a prefe ⁇ ed carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by
  • compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the compounds of the invention can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • the amount of the compound of the invention which will be effective in the treatment, inhibition and prevention of a disease or disorder associated with abe ⁇ ant expression and/or activity of a Therapeutic protein can be determined by standard clinical techniques.
  • in vitro assays may optionally be employed to help identify optimal dosage ranges.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the dosage administered to a patient is typically 0.1 mg kg to
  • the dosage administered to a patient is between 0.1 mg kg and 20 mg/kg of the patient's body weight, more preferably 1 mg kg to 10 mg kg of the patient's body weight.
  • human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible.
  • the dosage and frequency of administration of antibodies of the invention may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.
  • Labeled antibodies and derivatives and analogs thereof that bind a Therapeutic protein (or fragment or variant thereof) can be used for diagnostic purposes to detect, diagnose, or monitor diseases, disorders, and/or conditions associated with the abe ⁇ ant expression and/or activity of Therapeutic protein.
  • the invention provides for the detection of abe ⁇ ant expression of a Therapeutic protein, comprising (a) assaying the expression of the Therapeutic protein in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed Therapeutic protein expression level compared to the standard expression level is indicative of abe ⁇ ant expression.
  • the invention provides a diagnostic assay for diagnosing a disorder, comprising (a) assaying the expression of the Therapeutic protein in cells or body fluid of an individual using one or more antibodies specific to the Therapeutic protein or albumin fusion proteins comprising at least a fragment of variant of an antibody specific to a Therapeutic protein, and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed Therapeutic protein gene expression level compared to the standard expression level is indicative of a particular disorder.
  • the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
  • Antibodies of the invention or albumin fusion proteins comprising at least a fragment of variant of an antibody specific to a Therapeutic protein can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen et al., J. Cell . Biol. 105:3087-3096 (1987)).
  • Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA).
  • Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine
  • diagnosis comprises: a) administering (for example, parenterally, subcutaneously, or intraperitoneally) to a subject an effective amount of a labeled molecule which specifically binds to the polypeptide of interest; b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate at sites in the subject where the Therapeutic protein is expressed (and for unbound labeled molecule to be cleared to background level); c) determining background level; and d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with abe ⁇ ant expression of the therapeutic protein.
  • Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a
  • the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images.
  • the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc.
  • the labeled antibody, antibody fragment, or albumin fusion protein comprising at least a fragment or variant of an antibody that binds a Therapeutic protein will then preferentially accumulate at the location of cells which contain the specific Therapeutic protein.
  • In vivo tumor imaging is described in S.W. Burchiel et al., "Immunopharmacokinetics of
  • the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours.
  • the time interval following administration is 5 to 20 days or 5 to 10 days.
  • monitoring of the disease or disorder is carried out by repeating the method for diagnosing the disease or disease, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.
  • Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used.
  • CT computed tomography
  • PET position emission tomography
  • MRI magnetic resonance imaging
  • sonography sonography
  • the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S.
  • Patent No. 5,441,050 the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument.
  • the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • Antibodies that specifically detect the albumin fusion protein but not albumin or the therapeutic protein alone are a prefe ⁇ ed embodiment. These can be used to detect the albumin fusion protein as described throughout the specification.
  • kits that can be used in the above methods.
  • a kit comprises an antibody, preferably a purified antibody, in one or more containers.
  • the kits of the present invention contain a substantially isolated polypeptide comprising an epitope which is specifically immunoreactive with an antibody included in the kit.
  • the kits of the present invention further comprise a control antibody which does not react with the polypeptide of interest.
  • kits of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody may be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate).
  • a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate.
  • the kit is a diagnostic kit for use in screening serum containing antibodies specific against proliferative and/or cancerous polynucleotides and polypeptides.
  • a kit may ⁇ include a control antibody that does not react with the polypeptide of interest.
  • a kit may include a substantially isolated polypeptide antigen comprising an epitope which is specifically immunoreactive with at least one anti-polypeptide antigen antibody.
  • a kit includes means for detecting the binding of said antibody to the antigen (e.g., the antibody may be conjugated to a fluorescent compound such as fluorescein or rhodamine which can be detected by flow cytometry).
  • the kit may include a recombinantly produced or chemically synthesized polypeptide antigen.
  • the polypeptide antigen of the kit may also be attached to a solid support.
  • the detecting means of the above-described kit includes a solid support to which said polypeptide antigen is attached.
  • a kit may also include a non-attached reporter-labeled anti-human antibody.
  • binding of the antibody to the polypeptide antigen can be detected by binding of the said reporter-labeled antibody.
  • the invention includes a diagnostic kit for use in screening serum containing antigens of the polypeptide of the invention.
  • the diagnostic kit includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens, and means for detecting the binding of the polynucleotide or polypeptide antigen to the antibody.
  • the antibody is attached to a solid support.
  • the antibody may be a monoclonal antibody.
  • the detecting means of the kit may include a second, labeled monoclonal antibody. Alternatively, or in addition, the detecting means may include a labeled, competing antigen.
  • test serum is reacted with a solid phase reagent having a surface-bound antigen obtained by the methods of the present invention.
  • the reagent After binding with specific antigen antibody to the reagent and removing unbound serum components by washing, the reagent is reacted with reporter-labeled anti-human antibody to bind reporter to the reagent in proportion to the amount of bound anti-antigen antibody on the solid support.
  • the reagent is again washed to remove unbound labeled antibody, and the amount of reporter associated with the reagent is determined.
  • the reporter is an enzyme which is detected by incubating the solid phase in the presence of a suitable fluorometric, luminescent or colorimetric substrate (Sigma, St. Louis, MO).
  • the solid surface reagent in the above assay is prepared by known techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plate or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).
  • the invention provides an assay system or kit for carrying out this diagnostic method.
  • the kit generally includes a support with surface-bound recombinant antigens, and a reporter-labeled anti-human antibody for detecting surface-bound anti-antigen antibody.
  • the present invention relates generally to albumin fusion proteins and methods of treating, preventing, or ameliorating diseases or disorders.
  • albumin fusion proteins As used herein,
  • albumin fusion protein refers to a protein formed by the fusion of at least one molecule of albumin (or a fragment or variant thereof) to at least one molecule of a Therapeutic protein
  • An albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or a portion of a Therapeutic protein is joined in-frame with a polynucleotide encoding all or a portion of albumin) or to one another.
  • the Therapeutic protein and albumin protein, once part of the albumin fusion protein, may each be refe ⁇ ed to as a "portion",
  • region or "moiety” of the albumin fusion protein.
  • the invention provides an albumin fusion protein encoded by a polynucleotide or albumin fusion construct described in Table 1 or Table 2.
  • Polynucleotides encoding these albumin fusion proteins are also encompassed by the invention.
  • albumin fusion proteins of the invention include, but are not limited to, albumin fusion proteins encoded by a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof); a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof) generated as described in Table 1, Table 2 or in the Examples; or a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or
  • a region for initiation of transcription e.g., a promoter region, such as for example, a regulatable or inducible promoter, a constitutive promoter
  • a region for termination of transcription e.g., a leader sequence, and (5) a selectable marker.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein (e.g., as described in Table 1) and a serum albumin protein.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment of a Therapeutic protein and a serum albumin protein.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active variant of a Therapeutic protein and a serum albumin protein.
  • the serum albumin protein component of the albumin fusion protein is the mature portion of serum albumin.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein, and a biologically active and/or therapeutically active fragment of serum albumin.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a
  • the Therapeutic protein and a biologically active and/or therapeutically active variant of serum albumin are administered to the subject.
  • the Therapeutic protein portion of the albumin fusion protein is the mature portion of the Therapeutic protein.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment or variant of a Therapeutic protein and a biologically active and/or therapeutically active fragment or variant of serum albumin.
  • the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of a Therapeutic protein and the mature portion of serum albumin.
  • the albumin fusion protein comprises HA as the N-terminal portion, and a Therapeutic protein as the C-terminal portion.
  • a Therapeutic protein as the C-terminal portion may also be used.
  • the albumin fusion protein has a Therapeutic protein fused to both the N-terminus and the C-terminus of albumin.
  • the albumin fusion protein has a Therapeutic protein fused to both the N-terminus and the C-terminus of albumin.
  • Therapeutic proteins fused at the N- and C- termini are the same Therapeutic proteins. In an alternative prefe ⁇ ed embodiment, the Therapeutic proteins fused at the N- and C- termini are different Therapeutic proteins. In another prefe ⁇ ed embodiment, the Therapeutic proteins fused at the N- and C- termini are different Therapeutic proteins which may be used to treat or prevent the same or a related disease, disorder, or condition (e.g. as listed in the "Prefe ⁇ ed
  • the Therapeutic proteins fused at the N- and C- termini are different Therapeutic proteins which may be used to treat, ameliorate, or prevent diseases or disorders (e.g. as listed in the "Prefe ⁇ ed Indication Y" column of Table 1) which are known in the art to commonly occur in patients simultaneously, concu ⁇ ently, or consecutively, or which commonly occur in patients in association with one another.
  • Exemplary fusion proteins of the invention containing multiple Therapeutic protein portions fused at the N- and C- termini of albumin include, but are not limited to,
  • GCSF-HSA-EPO EPO-HSA-GCSF, IFNalpha-HSA-IL2, D 2-HSA-IFNalpha, GCSF-HSA-
  • E 2 E 2-HSA-GCSF, IL2-HSA-EPO, EPO-HSA-IL2, D 3-HSA-EPO, EPO-HSA-IL3,
  • GCSF-HSA-GMCSF GMCSF-HSA-GCSF, IL2-HSA-GMCSF, GMCSF-HSA-IL2, PTH-
  • PTH PTH-Calcitonin-HSA-PTH, or PTH-HSA-Calcitonin-PTH.
  • Albumin fusion proteins of the invention encompass proteins containing one, two, three, four, or more molecules of a given Therapeutic protein X or variant thereof fused to the N- or C- terminus of an albumin fusion protein of the invention, and/or to the N- and or
  • Molecules of a given Therapeutic protein X or variants thereof may be in any number of orientations, including, but not limited to, a 'head to head' orientation (e.g., wherein the N-terminus of one molecule of a Therapeutic protein X is fused to the N-terminus of another molecule of the Therapeutic protein X), or a 'head to tail' orientation (e.g., wherein the C-terminus of one molecule of a Therapeutic protein X is fused to the N-terminus of another molecule of Therapeutic protein X).
  • a 'head to head' orientation e.g., wherein the N-terminus of one molecule of a Therapeutic protein X is fused to the N-terminus of another molecule of the Therapeutic protein X
  • a 'head to tail' orientation e.g., wherein the C-terminus of one molecule of a Therapeutic protein X is fused to the N-terminus of another molecule of Therapeutic protein X.
  • one, two, three, or more tandemly oriented Therapeutic protein X polypeptides are fused to the N- or C- terminus of an albumin fusion protein of the invention, and/or to the N- and/or C- terminus of albumin or variant thereof.
  • one, two, three, four, five, or more tandemly oriented molecules of PTH are fused to the N- or C-terminus of albumin or variant thereof.
  • one, two, three, four, five, or more tandemly oriented molecules of PTH For example, one, two, three, four, five, or more tandemly oriented molecules of PTH
  • Exemplary fusion proteins of the invention containing multiple protein portions of PTH include, but are not limited to, PTH-PTH-HSA, HSA-PTH-PTH, PTH-PTH-PTH-HSA,
  • one, two, three, four, five, or more tandemly oriented molecules of GLP-1 are fused to the N- or C-terminus of albumin or variant thereof.
  • one, two, three, four, five, or more tandemly oriented molecules of GLP-1 For example, one, two, three, four, five, or more tandemly oriented molecules of GLP-1
  • Example the mutants disclosed in U.S. Patent No. 5,545,618, herein incorporated by reference in its entirety) are fused to the N- or C-terminus of albumin or variant thereof.
  • Exemplary fusion proteins of the invention containing multiple protein portions of GLP-1 include, but are not limited to, GL1-GLP1-HSA, HSA-GLP1-GLP1, GLPlmutant-
  • GLPlmutant-HSA HSA-GLPlmutant-GLPl mutant
  • GLPlmutant-GLPl-HSA HSA-GLPlmutant-GLPl mutant
  • GLPlmutant-GLPl GLPl, GLPl-GLPlmutant-HSA, or HSA-GLPl-GLPlmutant.
  • Particularly prefe ⁇ ed embodiments are GLP-1 tandem fusions such as construct ID #3070 and the protein encoded by such construct.
  • Albumin fusion proteins of the invention further encompass proteins containing one, two, three, four, or more molecules of a given Therapeutic protein X or variant thereof fused to the N- or C- terminus of an albumin fusion protein of the invention, and/or to the N- and or C- terminus of albumin or variant thereof, wherein the molecules are joined through peptide linkers. Examples include those peptide linkers described in U.S. Pat.
  • Albumin fusion proteins comprising multiple Therapeutic protein X polypeptides separated by peptide linkers may be produced using conventional recombinant DNA technology. Linkers are particularly important when fusing a small peptide to the large HSA molecule.
  • the peptide itself can be a linker by fusing tandem copies of the peptide (see for example GLP-1) or other known linkers can be used.
  • albumin fusion proteins of the invention may also be produced by fusing a Therapeutic protein X or variants thereof to the N-terminal and/or C-terminal of albumin or variants thereof in such a way as to allow the formation of intramolecular and/or intermolecular multimeric forms.
  • albumin fusion proteins may be in monomeric or multimeric forms (i.e., dimers, trimers, tetramers and higher multimers).
  • the Therapeutic protein portion of an albumin fusion protein may be in monomeric form or multimeric form (i.e., dimers, trimers, tetramers and higher multimers).
  • the Therapeutic protein portion of an albumin fusion protein is in multimeric form (i.e., dimers, trimers, tetramers and higher multimers), and the albumin protein portion is in monomeric form.
  • albumin fusion proteins of the invention may also be produced by inserting the Therapeutic protein or peptide of interest
  • a Therapeutic protein X as disclosed in Table 1, or an antibody that binds a Therapeutic protein or a fragment or variant thereof into an internal region of HA.
  • the loops as determined from the crystal structure of HA (PDB identifiers 1 AO6, 1BJ5, 1BKE, 1BM0,
  • loops are useful for the insertion, or internal fusion, of therapeutically active peptides, particularly those requiring a secondary structure to be functional, or Therapeutic proteins, to essentially generate an albumin molecule with specific biological activity.
  • Loops in human albumin structure into which peptides or polypeptides may be inserted to generate albumin fusion proteins of the invention include: Val54-Asn61, Thr76-
  • peptides or polypeptides are inserted into the
  • Peptides to be inserted may be derived from either phage display or synthetic peptide libraries screened for specific biological activity or from the active portions of a molecule with the desired function. Additionally, random peptide libraries may be generated within particular loops or by insertions of randomized peptides into particular loops of the
  • Such library(s) could be generated on HA or domain fragments of HA by one of the following methods:
  • N-, C- or N- and C- terminal peptide/protein fusions in addition to (a) and/or
  • the HA or HA domain fragment may also be made multifunctional by grafting the peptides derived from different screens of different loops against different targets into the same HA or HA domain fragment.
  • peptides inserted into a loop of human serum albumin are peptide fragments or peptide variants of the Therapeutic proteins disclosed in
  • the invention encompasses albumin fusion proteins which comprise peptide fragments or peptide variants at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 35, or at least 40 amino acids in length inserted into a loop of human serum albumin.
  • albumin fusion proteins which comprise peptide fragments or peptide variants at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least
  • albumin fusion proteins which comprise peptide fragments or peptide variants at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least
  • Therapeutic Y can be inserted into the albumin loops.
  • albumin fusion proteins of the invention may have one
  • HA-derived region and one Therapeutic protein-derived region may be used to make an albumin fusion protein of the invention.
  • Multiple regions of each protein may be used to make an albumin fusion protein of the invention.
  • more than one Therapeutic protein may be used to make an albumin fusion protein of the invention.
  • a Therapeutic protein may be fused to both the N- and C-terminal ends of the HA.
  • the Therapeutic protein portions may be the same or different Therapeutic protein molecules.
  • the structure of bifunctional albumin fusion proteins maybe represented as: X-HA-Y or Y-HA-X.
  • an anti-BLySTM scFv-HA-IFN ⁇ -2b fusion may be prepared to modulate the immune response to IFN ⁇ -2b by anti-BLySTM scFv.
  • An alternative is making a bi (or even multi) functional dose of HA-fusions e.g. HA-IFN ⁇ -2b fusion mixed with HA- anti-BLySTM scFv fusion or other HA-fusions in various ratio's depending on function, half- life etc.
  • Bi- or multi-functional albumin fusion proteins may also be prepared to target the Therapeutic protein portion of a fusion to a target organ or cell type via protein or peptide at the opposite terminus of HA.
  • the peptides could be obtained by screening libraries constructed as fusions to the N-, C- or N- and C- termini of HA, or domain fragment of HA, of typically 6, 8, 12, 20 or 25 or X bond (where X is an amino acid (aa) and n equals the number of residues) randomized amino acids, and in which all possible combinations of amino acids were represented.
  • X is an amino acid (aa) and n equals the number of residues
  • peptides may be selected in situ on the HA molecule and the properties of the peptide would therefore be as selected for rather than, potentially, modified as might be the case for a peptide derived by any other method then being attached to HA.
  • the albumin fusion proteins of the invention may include a linker peptide between the fused portions to provide greater physical separation between the moieties and thus maximize the accessibility of the Therapeutic protein portion, for instance, for binding to its cognate receptor.
  • the linker peptide may consist of amino acids such that it is flexible or more rigid.
  • the linker sequence may be cleavable by a protease or chemically to yield the growth hormone related moiety.
  • the protease is one which is produced naturally by the host, for example the S. cerevisiae protease kex2 or equivalent proteases.
  • the albumin fiision proteins of the invention may have the following formula R1-L-R2; R2-L-R1; or R1-L-R2-L-R1, wherein Rl is at least one Therapeutic protein, peptide or polypeptide sequence, and not necessarily the same
  • Therapeutic protein L is a linker and R2 is a serum albumin sequence.
  • Albumin fusion proteins of the invention comprising a Therapeutic protein have extended shelf life compared to the shelf life the same
  • Shelf-life typically refers to the time period over which the therapeutic activity of a Therapeutic protein in solution or in some other storage formulation, is stable without undue loss of therapeutic activity.
  • Therapeutic proteins are highly labile in their unfused state. As described below, the typical shelf-life of these Therapeutic proteins is markedly prolonged upon incorporation into the albumin fusion protein of the invention.
  • Albumin fusion proteins of the invention with "prolonged” or “extended” shelf-life exhibit greater therapeutic activity relative to a standard that has been subjected to the same storage and handling conditions.
  • the standard may be the unfused full-length Therapeutic protein.
  • the Therapeutic protein portion of the albumin fusion protein is an analog, a variant, or is otherwise altered or does not include the complete sequence for that protein, the prolongation of therapeutic activity may alternatively be compared to the unfused equivalent of that analog, variant, altered peptide or incomplete sequence.
  • an albumin fusion protein of the invention may retain greater than about 100% of the therapeutic activity, or greater than about 105%, 110%, 120%, 130%, 150% or 200% of the therapeutic activity of a standard when subjected to the same storage and handling conditions as the standard when compared at a given time point.
  • Shelf-life may also be assessed in terms of therapeutic activity remaining after storage, normalized to therapeutic activity when storage began.
  • Albumin fusion proteins of the invention with prolonged or extended shelf-life as exhibited by prolonged or extended therapeutic activity may retain greater than about 50% of the therapeutic activity, about 60%, 70%, 80%, or 90% or more of the therapeutic activity of the equivalent unfused Therapeutic protein when subjected to the same conditions.
  • an albumin fusion protein of the invention comprising hGH fused to the full length HA sequence may retain about 80% or more of its original activity in solution for periods of up to 5 weeks or more under various temperature conditions.
  • the albumin fusion proteins of the invention may be produced as recombinant molecules by secretion from yeast, a microorganism such as a bacterium, or a human or animal cell line.
  • the polypeptide is secreted from the host cells.
  • a particular embodiment of the invention comprises a DNA construct encoding a signal sequence effective for directing secretion in yeast, particularly a yeast-derived signal sequence (especially one which is homologous to the yeast host), and the fused molecule of the first aspect of the invention, there being no yeast-derived pro sequence between the signal and the mature polypeptide.
  • Saccharomyces cerevisiae invertase signal is a prefe ⁇ ed example of a yeast-derived signal sequence.
  • the present invention also includes a cell, preferably a yeast cell transformed to express an albumin fusion protein of the invention.
  • a cell preferably a yeast cell transformed to express an albumin fusion protein of the invention.
  • the present invention also contemplates a culture of those cells, preferably a monoclonal (clonally homogeneous) culture, or a culture derived from a monoclonal culture, in a nutrient medium. If the polypeptide is secreted, the medium will contain the polypeptide, with the cells, or without the cells if they have been filtered or centrifuged away.
  • Many expression systems are known and may be used, including bacteria (for example E. coli and
  • yeasts for example Saccharomyces cerevisiae, Kluyveromyces lactis and
  • Pichia pastoris filamentous fungi (for example Aspergillus), plant cells, animal cells and insect cells.
  • Prefe ⁇ ed yeast strains to be used in the production of albumin fusion proteins are D88, DXY1 and BXP10.
  • D88 [leu2-3, leu2-122, canl, pral, ubc4] is a derivative of parent strain AH22his + (also known as DB1; see, e.g., Sleep et al. Biotechnology 8:42-46
  • the strain contains a leu2 mutation which allows for auxotropic selection of 2 micron-based plasmids that contain the LEU2 gene. D88 also exhibits a derepression of
  • PRB1 in glucose excess.
  • the PRB1 promoter is normally controlled by two checkpoints that monitor glucose levels and growth stage. The promoter is activated in wild type yeast upon glucose depletion and entry into stationary phase. Strain D88 exhibits the repression by glucose but maintains the induction upon entry into stationary phase.
  • the PRA1 gene encodes a yeast vacuolar protease, YscA endoprotease A, that is localized in the ER.
  • UBC4 gene is in the ubiquitination pathway and is involved in targeting short lived and abnormal proteins for ubiquitin dependant degradation. Isolation of this ubc4 mutation was found to increase the copy number of an expression plasmid in the cell and cause an increased level of expression of a desired protein expressed from the plasmid (see, e.g., International
  • DXY1 a derivative of D88, has the following genotype: [leu2-3, leu2-122, canl, pral, ubc4, ura3::yap3].
  • this strain also has a knockout of the YAP3 protease. This protease causes cleavage of mostly di-basic residues (RR, RK, KR, KK) but can also promote cleavage at single basic residues in proteins. Isolation of this yap3 mutation resulted in higher levels of full length HSA production (see, e.g., U.S. Patent No. 5,965,386 and Kerry- Williams et al., Yeast 14:161-169
  • BXP10 has the following genotype: leu2-3, leu2-122, canl, pral, ubc4, ura3, yap3::URA3, lys2, hspl50::LYS2, pmtl::URA3.
  • this strain also has a knockout of the PMT1 gene and the HSP150 gene.
  • the PMT1 gene is a member of the evolutionarily conserved family of dolichyl-phosphate-D-mannose protein O-mannosyltransferases (Pmts).
  • Pmts dolichyl-phosphate-D-mannose protein O-mannosyltransferases
  • the transmembrane topology of Pmtlp suggests that it is an integral membrane protein of the endoplasmic reticulum with a role in O-linked glycosylation.
  • This mutation serves to reduce/eliminate O-linked glycosylation of HSA fusions (see, e.g., International Publication No. WO00/44772, hereby incorporated in its entirety by reference herein).
  • Hspl50 protein is inefficiently separated from rHA by ion exchange chromatography.
  • the mutation in the HSP150 gene removes a potential contaminant that has proven difficult to remove by standard purification techniques. See, e.g., U.S. Patent No. 5,783,423, hereby incorporated in its entirety by reference herein.
  • the desired protein is produced in conventional ways, for example from a coding sequence inserted in the host chromosome or on a free plasmid.
  • the yeasts are transformed with a coding sequence for the desired protein in any of the usual ways, for example electroporation. Methods for transformation of yeast by electroporation are disclosed in Becker & Guarente (1990) Methods Enzymol. 194, 182.
  • Successfully transformed cells i.e., cells that contain a DNA construct of the present invention, can be identified by well known techniques. For example, cells resulting from the introduction of an expression construct can be grown to produce the desired polypeptide. Cells can be harvested and lysed and their DNA content examined for the presence of the DNA using a method such as that described by Southern (1975) J. Mol. Biol.
  • the presence of the protein in the supernatant can be detected using antibodies.
  • Useful yeast plasmid vectors include pRS403-406 and pRS413-416 and are generally available from Stratagene Cloning Systems, La Jolla, CA 92037, USA.
  • Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integrating plasmids (Yips) and incorporate the yeast selectable markers HIS3, 7RP1, LEU2 and URA3.
  • Plasmids pRS413-416 are Yeast Integrating plasmids
  • Prefe ⁇ ed vectors for making albumin fusion proteins for expression in yeast include pPPC0005, pScCHSA, pScNHSA, and pC4:HSA which are described in detail in
  • FIG. 2 shows a map of the pPPC0005 plasmid that can be used as the base vector into which polynucleotides encoding Therapeutic proteins may be cloned to form HA- fusions. It contains a PRB1 S. cerevisiae promoter (PRBlp), a Fusion leader sequence (FL), DNA encoding HA (rHA) and an ADH1 S. cerevisiae terminator sequence.
  • the sequence of the fusion leader sequence consists of the first 19 amino acids of the signal peptide of human serum albumin (SEQ ID NO: 1094) and the last five amino acids of the mating factor alpha 1 promoter (SLDKR, see EP-A-387 319 which is hereby incorporated by reference in its entirety).
  • the plasmids, pPPC0005, pScCHSA, pScNHSA, and pC4:HSA were deposited on April 11, 2001 at the American Type Culture Collection, 10801 University Boulevard, Manassas, Virginia 20110-2209 and given accession numbers ATCC PTA-3278, PTA-3276, PTA-3279, and PTA-3277, respectively.
  • Another vector useful for expressing an albumin fusion protein in yeast the pSAC35 vector which is described in Sleep et al, BioTechnology 8:42 (1990) which is hereby incorporated by reference in its entirety.
  • Another yeast promoter that can be used to express the albumin fusion protein is the MET25 promoter.
  • the Met25 promoter is 383 bases long (bases -382 to -1) and the genes expressed by this promoter are also known as Metl5, Metl7, and YLR303W.
  • a prefe ⁇ ed embodiment uses the sequence below, where, at the 5' end of the sequence below, the Not 1 site used in the cloning is underlined and at the 3' end, the ATG start codon is underlined:
  • a variety of methods have been developed to operably link DNA to vectors via complementary cohesive termini. For instance, complementary homopolymer tracts can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules.
  • Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors.
  • the DNA segment, generated by endonuclease restriction digestion is treated with bacteriophage T4 DNA polymerase or E. coli DNA polymerase I, enzymes that remove protruding, gamma-single-stranded termini with their 3' 5'-exonucleolytic activities, and fill in recessed 3'-ends with their polymerizing activities.
  • blunt-ended DNA segments are then incubated with a large molar excess of linker molecules in the presence of an enzyme that is able to catalyze the ligation of blunt-ended
  • DNA molecules such as bacteriophage T4 DNA ligase.
  • the products of the reaction are
  • DNA segments carrying polymeric linker sequences at their ends are then cleaved with the appropriate restriction enzyme and ligated to an expression vector that has been cleaved with an enzyme that produces termini compatible with those of the DNA segment.
  • a desirable way to modify the DNA in accordance with the invention is to use the polymerase chain reaction as disclosed by Saiki et al. (1988) Science 239, 487-491.
  • the DNA to be enzymatically amplified is flanked by two specific oligonucleotide primers which themselves become incorporated into the amplified DNA.
  • the specific primers may contain restriction endonuclease recognition sites which can be used for cloning into expression vectors using methods known in the art.
  • Exemplary genera of yeast contemplated to be useful in the practice of the present invention as hosts for expressing the albumin fusion proteins are Pichia (Hansenula),
  • Prefe ⁇ ed genera are those selected from the group consisting of Saccharomyces, Schizosaccharomyces, Kluyveromyces, Pichia and Torulaspora.
  • Saccharomyces spp. are S. cerevisiae, S. italicus and S. rouxii.
  • Examples of Kluyveromyces spp. are K. fragilis, K. lactis and K. marxianus.
  • a suitable Torulaspora species is T. delbrueckii.
  • Examples of Pichia (Hansenula) spp. are P. angusta (formerly H. polymorpha), P. anomala (formerly H. anomala) and P. pastoris.
  • Saccharomyces include S. cerevisiae, S. italicus, S. diastaticus, and Zygosaccharomyces rouxii.
  • Saccharomyces include S. cerevisiae, S. italicus, S. diastaticus, and Zygosaccharomyces rouxii.
  • Prefe ⁇ ed exemplary species of Saccharomyces include S. cerevisiae, S. italicus, S. diastaticus, and Zygosaccharomyces rouxii.
  • Kluyveromyces include K. fragilis and K. lactis.
  • Prefe ⁇ ed exemplary species of Hansenula include H. polymorpha (now Pichia angusta), H. anomala (now Pichia anomala), and Pichia capsulata. Additional prefe ⁇ ed exemplary species of Pichia include P. pastoris.
  • Prefe ⁇ ed exemplary species of Aspergillus include A. niger and A. nidulans.
  • Prefe ⁇ ed exemplary species of Yarrowia include Y. lipolytica.
  • Many prefe ⁇ ed yeast species are available from the ATCC. For example, the following prefe ⁇ ed yeast species are available from the ATCC and are useful in the expression of albumin fusion proteins: Saccharomyces cerevisiae
  • Saccharomyces cerevisiae ⁇ ansen Saccharomorph strain BY4743 pmtl mutant (ATCC Accession No. 4023792); Saccharomyces cerevisiae ⁇ ansen, teleomorph
  • Kluyveromyces lactis (Dombrowski) van der Walt, teleomorph (ATCC Accession No.
  • Suitable promoters for S. cerevisiae include those associated with the PGKI gene, GAL1 or GAL10 genes, CYCI, P ⁇ O5, TRPI, ADHI, ADH2, the genes for glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, triose phosphate isomerase, phosphoglucose isomerase, glucokinase, alpha-mating factor pheromone, [a mating factor pheromone], the PRBI promoter, the GUT2 promoter, the GPDI promoter, and hybrid promoters involving hybrids of parts of 5' regulatory regions with parts of 5' regulatory regions of other promoters or with upstream activation sites (e.g.
  • Convenient regulatable promoters for use in Schizosaccharomyces pombe are the thiamine-repressible promoter from the nmt gene as described by Maundrell (1990) J. Biol. Chem. 265, 10857-10864 and the glucose repressible jbpl gene promoter as described by Hoffman & Winston (1990) Genetics 124, 807-816.
  • Pichia expression kits are commercially available from Invitrogen BV, Leek, Netherlands, and hrvitrogen Corp., San Diego, California.
  • Suitable promoters include AOXI and AOX2.
  • Gleeson et al. (1986) j. Gen. Microbiol. 132, 3459-3465 include information on Hansenula vectors and transformation, suitable promoters being MOX1 and FMD1; whilst EP 361 991, Fleer et al. (1991) and other- publications from Rhone-Poulenc Rorer teach how to express foreign proteins in Kluyveromyces spp., a suitable promoter being PGKI.
  • the transcription termination signal is preferably the 3' flanking sequence of a eukaryotic gene which contains proper signals for transcription termination and polyadenylation.
  • Suitable 3' flanking sequences may, for example, be those of the gene naturally linked to the expression control sequence used, i.e. may co ⁇ espond to the promoter. Alternatively, they may be different in which case the termination signal of the S. cerevisiae ADHI gene is prefe ⁇ ed.
  • the desired albumin fusion protein may be initially expressed with a secretion leader sequence, which may be any leader effective in the yeast chosen.
  • Leaders useful in yeast include any of the following: a) the MPIF-1 signal sequence (e.g., amino acids 1-21 of GenBank Accession number AAB51134) MKVSVAALSCLMLVTALGSQA (SEQ ID NO:2132) b) the stanniocalcin signal sequence (MLQNSAVLLLLVISASA, SEQ ID NO: 1054) c) the pre-pro region of the HSA signal sequence (e.g., MKWVTFISLLFLFSSAYSRGVFRR, SEQ ID NO: 1176) d) the pre region of the HSA signal sequence (e.g., MKWVTFISLLFLFSSAYS, SEQ ID NO: 1177) or variants thereof, such as, for example, MKWVSFISLLFLFSSAYS, (SEQ ID NO:1168) e) the invertase signal sequence (e.g., MLL
  • AVLPFSNSTNNGLLFINTTIASIAAKEEGVSLDKR SEQ ID NO: 1109
  • K. lactis killer toxin leader sequence h) a hybrid signal sequence (e.g., MKWVSFISLLFLFSSAYSRSLEKR, SEQ ID NO: 116)
  • HSA/MF ⁇ -1 hybrid signal sequence also known as HSA kex2
  • Fibulin B precursor signal sequence e.g., the Fibulin B precursor signal sequence
  • MERAAPSRRVPLPLLLLGGLALLAAGVDA SEQ ID NO: 1096
  • the clusterin precursor signal sequence e.g., MMKTLLLFVGLLLTWESGQVLG
  • insulin-like growth factor-binding protein 4 signal sequence e.g., the insulin-like growth factor-binding protein 4 signal sequence
  • MLPLCLVAALLLAAGPGPSLG SEQ ID NO: 1098
  • variants of the pre-pro-region of the HSA signal sequence such as, for example,
  • MKWVTFISLLFLFGGVLGDLHKS (SEQ ID NO:l 105) p) a consensus signal sequence (MPTWAWWLFLVLLLALWAPARG, SEQ ID NO:
  • acid phosphatase (PH05) leader e.g., MFKSVVYSILAASLANA SEQ ID NO: 1055
  • SGGLDWGLISMAKR (SEQ ID NO:2128) ff) A modified TA57 propeptide leader variant #2 -
  • the present invention also relates to vectors containing a polynucleotide encoding an albumin fusion protein of the present invention, host cells, and the production of albumin fusion proteins by synthetic and recombinant techniques.
  • the vector may be, for example, a phage, plasmid, viral, or retroviral vector.
  • Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.
  • the polynucleotides encoding albumin fusion proteins of the invention may be joined to a vector containing a selectable marker for propagation in a host.
  • a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

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US10/775,204 US7141547B2 (en) 2001-12-21 2004-02-11 Albumin fusion proteins comprising GLP-1 polypeptides
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US11/495,624 US20080004206A1 (en) 2001-12-21 2006-07-31 Albumin fusion proteins
US11/714,841 US20070244047A1 (en) 2001-12-21 2007-03-07 Albumin fusion proteins
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US11/929,939 US8211439B2 (en) 2001-12-21 2007-10-30 Albumin fusion proteins comprising insulin polypeptides
US11/929,828 US8012464B2 (en) 2001-12-21 2007-10-30 G-CSF-albumin fusion proteins
US11/929,714 US20080161243A1 (en) 2001-12-21 2007-10-30 Albumin Fusion Proteins
US11/932,823 US20080194481A1 (en) 2001-12-21 2007-10-31 Albumin Fusion Proteins
US12/793,652 US20100291033A1 (en) 2001-12-21 2010-06-03 Albumin Fusion Proteins
US12/793,658 US8287859B2 (en) 2001-12-21 2010-06-03 Methods of reducing toxicity and effects of cocaine by administering a butyrylcholinesterase (BChE)-albumin fusion protein
US12/836,447 US8071539B2 (en) 2001-12-21 2010-07-14 Albumin fusion proteins
US13/078,827 US8513189B2 (en) 2001-12-21 2011-04-01 Albumin fusion proteins
US13/078,708 US8252739B2 (en) 2001-12-21 2011-04-01 Albumin fusion proteins
US13/929,310 US8993517B2 (en) 2001-12-21 2013-06-27 Albumin fusion proteins
US13/966,186 US20140179596A1 (en) 2001-12-21 2013-08-13 Albumin fusion proteins
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Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005026392A2 (en) * 2003-09-11 2005-03-24 Liat Mintz Compositions, reagents and kits for and methods of diagnosing, monitoring and treating obesity and/or diabetes
WO2005054286A3 (en) * 2003-12-03 2006-11-30 Delta Biotechnology Ltd Interleukin-11 fusion proteins
US7189690B2 (en) 2001-12-21 2007-03-13 Human Genome Sciences, Inc. Albumin fusion proteins
JP2007508332A (ja) * 2003-10-17 2007-04-05 ノボ　ノルディスク　アクティーゼルスカブ 併用療法
WO2007056681A2 (en) 2005-11-04 2007-05-18 Smithkline Beecham Corporation Methods for administering hypoglycemic agents
WO2007064437A2 (en) * 2005-11-10 2007-06-07 Receptor Biologix, Inc. Methods for production of receptor and ligand isoforms
JP2007522806A (ja) * 2004-02-09 2007-08-16 ヒューマン　ジノーム　サイエンシーズ，　インコーポレイテッド アルブミン融合蛋白質
US7271149B2 (en) 2000-12-07 2007-09-18 Eli Lilly And Company GLP-1 fusion proteins
US20070219131A1 (en) * 2004-04-15 2007-09-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
WO2007112940A2 (en) * 2006-03-31 2007-10-11 Ablynx N.V. Albumin-derived amino acid sequence, use thereof for increasing the half-life of therapeutic proteins and of other therapeutic compounds and entities, and constructs comprising the same
US7371384B2 (en) 2004-07-20 2008-05-13 Genentech, Inc. Compositions and methods of using angiopoietin-like 4 protein antibody
EP1924596A2 (en) * 2005-08-12 2008-05-28 Human Genome Sciences, Inc. Albumin fusion proteins
US7393823B1 (en) 1999-01-20 2008-07-01 Oregon Health And Science University HER-2 binding antagonists
US20080260746A1 (en) * 2005-11-24 2008-10-23 Laboratoires Serono Sa Erythropoietin Polypeptides and Uses Thereof
EP2054437A2 (en) * 2006-08-07 2009-05-06 Teva Biopharmaceuticals USA, Inc. Albumin-insulin fusion proteins
WO2009058322A1 (en) 2007-10-31 2009-05-07 Human Genome Sciences, Inc. Albumin fusion proteins
US7572451B2 (en) 2004-10-25 2009-08-11 Cytos Biotechnology Ag Gastric inhibitory polypeptide (GIP) antigen arrays and uses thereof
WO2009121804A1 (en) 2008-03-31 2009-10-08 Glaxo Group Limited Drug fusions and conjugates
US7632983B2 (en) 2000-07-31 2009-12-15 Biolex Therapeutics, Inc. Expression of monoclonal antibodies in duckweed
WO2010020777A2 (en) * 2008-08-19 2010-02-25 The Secretary Of State For Defence Dstl Protein expression
US7740846B2 (en) 2004-07-20 2010-06-22 Genentech, Inc. Inhibitors of angiopoietin-like 4 protein, combinations, and their use
US7785599B2 (en) 2000-04-12 2010-08-31 Human Genome Sciences, Inc. Albumin fusion proteins
US7799759B2 (en) 2001-12-21 2010-09-21 Human Genome Sciences, Inc. Albumin fusion proteins
WO2010108937A2 (en) 2009-03-27 2010-09-30 Glaxo Group Limited Drug fusions and conjugates
WO2011039096A1 (en) 2009-09-30 2011-04-07 Glaxo Group Limited Drug fusions and conjugates with extended half life
EP2332563A2 (en) 2004-10-13 2011-06-15 The Washington University Use of BAFF to treat sepsis
US8022270B2 (en) 2000-07-31 2011-09-20 Biolex Therapeutics, Inc. Expression of biologically active polypeptides in duckweed
WO2011124718A1 (en) * 2010-04-09 2011-10-13 Novozymes A/S Albumin derivatives and variants
US8084200B2 (en) 2002-11-15 2011-12-27 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
AU2005211776B2 (en) * 2004-02-11 2012-02-02 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs and polypeptides comprising the same
WO2012059486A1 (en) 2010-11-01 2012-05-10 Novozymes Biopharma Dk A/S Albumin variants
US8231878B2 (en) 2001-03-20 2012-07-31 Cosmo Research & Development S.P.A. Receptor trem (triggering receptor expressed on myeloid cells) and uses thereof
WO2012136790A1 (en) 2011-04-07 2012-10-11 Glaxo Group Limited Compositions comprising fusion proteins or conjugates with an improved half -life
WO2012136792A2 (en) 2011-04-07 2012-10-11 Glaxo Group Limited Cck compositions
WO2012150319A1 (en) 2011-05-05 2012-11-08 Novozymes Biopharma Dk A/S Albumin variants
US8334365B2 (en) 2006-06-07 2012-12-18 Human Genome Sciences, Inc. Albumin fusion proteins
WO2013006675A1 (en) 2011-07-05 2013-01-10 Novozymes Biopharma Uk Limited Albumin formulation and use
AU2007227202B2 (en) * 2006-03-21 2013-08-22 Amylin Pharmaceuticals, Llc Peptide-peptidase inhibitor conjugates and methods of using same
WO2013135896A1 (en) 2012-03-16 2013-09-19 Novozymes Biopharma Dk A/S Albumin variants
US8541373B2 (en) 2009-12-08 2013-09-24 Teva Pharmaceutical Industries Ltd. BChE albumin fusions for the treatment of cocaine abuse
US20130261025A1 (en) * 2007-02-22 2013-10-03 Lauri Diehl Methods for detecting inflammatory bowel disease
WO2013171570A1 (en) 2012-05-16 2013-11-21 Glaxo Group Limited Polypeptide loaded poca nanoparticles for oral administration
US8598314B2 (en) 2007-09-27 2013-12-03 Amylin Pharmaceuticals, Llc Peptide-peptidase-inhibitor conjugates and methods of making and using same
US8604185B2 (en) 2004-07-20 2013-12-10 Genentech, Inc. Inhibitors of angiopoietin-like 4 protein, combinations, and their use
US8642542B2 (en) 1995-12-30 2014-02-04 Novozymes Biopharma Dk A/S Recombinant fusion proteins to growth hormone and serum albumin
WO2014012082A3 (en) * 2012-07-13 2014-04-03 Zymeworks Inc. Multivalent heteromultimer scaffold design an constructs
US8765915B2 (en) 2006-02-06 2014-07-01 Csl Behring Gmbh Modified coagulation factor VIIa with extended half-life
WO2014125082A1 (en) 2013-02-16 2014-08-21 Novozymes Biopharma Dk A/S Pharmacokinetic animal model
EP2769990A2 (en) 2004-12-02 2014-08-27 Domantis Limited Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY
US8981061B2 (en) 2001-03-20 2015-03-17 Novo Nordisk A/S Receptor TREM (triggering receptor expressed on myeloid cells) and uses thereof
US8993519B2 (en) 2009-01-16 2015-03-31 Teva Pharmaceutical Industries Ltd. Method of treatment for neutropenia using stable formulations of recombinant human albumin-human granulocyte colony stimulating factor
US9000127B2 (en) 2012-02-15 2015-04-07 Novo Nordisk A/S Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1)
EP2860260A1 (en) * 2008-04-11 2015-04-15 Merrimack Pharmaceuticals, Inc. Human serum albumin linkers and conjugates thereof
EP2423222B1 (en) 2007-01-30 2015-04-29 Epivax, Inc. Regulatory t cell epitopes, compositions and uses thereof
US9265812B2 (en) 2008-09-17 2016-02-23 Chiasma, Inc. Pharmaceutical compositions and related methods of delivery
US9273111B2 (en) 2004-11-29 2016-03-01 Universite De Lorraine Therapeutic TREM-1 peptides
US9345766B2 (en) 2012-08-30 2016-05-24 Merrimack Pharmaceuticals, Inc. Combination therapies comprising anti-ERBB3 agents
EP2931298A4 (en) * 2012-12-12 2016-07-06 Teva Pharma FUSION OF HUMAN GROWTH HORMONES AND ALBUMIN, AND FORMULATION THEREOF AND USE THEREOF
US9545086B2 (en) 1999-01-25 2017-01-17 Biogen Ma Inc. BAFF, inhibitors thereof and their use in the modulation of B-cell response and treatment of autoimmune disorders
US9550830B2 (en) 2012-02-15 2017-01-24 Novo Nordisk A/S Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1)
US9663568B2 (en) 2012-02-15 2017-05-30 Novo Nordisk A/S Antibodies that bind peptidoglycan recognition protein 1
WO2018082758A1 (en) 2016-11-04 2018-05-11 Aarhus Universitet Identification and treatment of tumors characterized by an overexpression of the neonatal fc receptor
US10155803B2 (en) 2011-03-03 2018-12-18 Zymeworks Inc. Multivalent heteromultimer scaffold design and constructs
US10179814B2 (en) 2014-07-17 2019-01-15 Novo Nordisk A/S Site directed mutagenesis of TREM-1 antibodies for decreasing viscosity
US10501524B2 (en) 2012-11-08 2019-12-10 Albumedix Ltd Albumin variants
US10633428B2 (en) 2015-08-20 2020-04-28 Albumedix Ltd Albumin variants and conjugates
US10654912B2 (en) 2015-09-08 2020-05-19 Jcr Pharmaceuticals Co., Ltd. Human serum albumin mutant
US10696732B2 (en) 2009-10-30 2020-06-30 Albumedix, Ltd Albumin variants
US10711050B2 (en) 2011-11-18 2020-07-14 Albumedix Ltd Variant serum albumin with improved half-life and other properties
WO2021044361A1 (en) 2019-09-06 2021-03-11 Novartis Ag Therapeutic fusion proteins
US10968267B2 (en) 2016-03-14 2021-04-06 Jcr Pharmaceuticals Co., Ltd. Serum albumin-20K growth hormone fusion protein
WO2021106016A1 (en) * 2019-11-27 2021-06-03 Revelations Biotech Pvt Ltd Nucleic acids, vectors, host cells and methods for production of beta-fructofuranosidase from aspergillus niger
WO2021106017A1 (en) * 2019-11-27 2021-06-03 Revelations Biotech Pvt Ltd Nucleic acids, vectors, host cells and methods for production of fructosyltransferase from aspergillus japonicus
WO2021111143A1 (en) 2019-12-04 2021-06-10 Albumedix Limited Methods and compositions produced thereby
US11155618B2 (en) 2018-04-02 2021-10-26 Bristol-Myers Squibb Company Anti-TREM-1 antibodies and uses thereof
US11338011B2 (en) 2015-02-03 2022-05-24 Amryt Endo, Inc. Method of treating diseases
US11555061B2 (en) 2009-02-11 2023-01-17 Albumedix, Ltd Albumin variants and conjugates
US11890316B2 (en) 2020-12-28 2024-02-06 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods

Families Citing this family (266)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060084082A1 (en) * 1997-03-07 2006-04-20 Human Genome Sciences, Inc. 186 human secreted proteins
US7625859B1 (en) 2000-02-16 2009-12-01 Oregon Health & Science University HER-2 binding antagonists
US20050100991A1 (en) * 2001-04-12 2005-05-12 Human Genome Sciences, Inc. Albumin fusion proteins
US20050244931A1 (en) * 2001-04-12 2005-11-03 Human Genome Sciences, Inc. Albumin fusion proteins
US7507413B2 (en) * 2001-04-12 2009-03-24 Human Genome Sciences, Inc. Albumin fusion proteins
WO2005003296A2 (en) * 2003-01-22 2005-01-13 Human Genome Sciences, Inc. Albumin fusion proteins
KR101271635B1 (ko) * 2001-12-21 2013-06-12 휴먼 게놈 사이언시즈, 인코포레이티드 알부민 융합 단백질
US20060241027A1 (en) * 2002-02-07 2006-10-26 Hans-Peter Hauser Hiv inhibiting proteins
US20050222023A1 (en) * 2002-02-07 2005-10-06 Hans-Peter Hauser Albumin-fused kunitz domain peptides
AU2003244516A1 (en) * 2002-02-07 2003-09-02 Novozymes Delta Limited Hiv inhibiting proteins
CN101172091B (zh) * 2007-09-25 2011-04-27 北京美福源生物医药科技有限公司 含人血清白蛋白与皮肤细胞生长因子的融合蛋白护肤产品制备工艺和用途
CN1241946C (zh) * 2002-07-01 2006-02-15 美国福源集团 对多种细胞具刺激增生作用的人血清白蛋白重组融合蛋白
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
EP1631496B1 (en) 2003-04-28 2014-02-26 Medical Instill Technologies, Inc. Container with valve assembly for filling and dispensing substances, and apparatus and method for filling
TWI353991B (en) 2003-05-06 2011-12-11 Syntonix Pharmaceuticals Inc Immunoglobulin chimeric monomer-dimer hybrids
US20070161087A1 (en) * 2003-05-29 2007-07-12 Wolfgang Glaesner Glp-1 fusion proteins
AU2004251145C1 (en) * 2003-06-12 2011-04-14 Eli Lilly And Company GLP-1 analog fusion proteins
NZ550320A (en) 2004-04-15 2010-02-26 Chiasma Inc Compositions capable of facilitating penetration across a biological barrier
AU2005235635B2 (en) 2004-04-21 2010-11-18 Alexion Pharmaceuticals, Inc. Bone delivery conjugates and method of using same to target proteins to bone
MXPA06012472A (es) * 2004-04-27 2007-01-26 Vital Therapies Inc Sistema y metodo de desintoxicacion metabolica.
EP1828241A1 (en) * 2004-12-23 2007-09-05 Laboratoires Serono S.A. G-csf polypeptides and uses thereof
WO2006083761A2 (en) 2005-02-03 2006-08-10 Alza Corporation Solvent/polymer solutions as suspension vehicles
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
WO2007000769A2 (en) * 2005-06-29 2007-01-04 Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science RECOMBINANT INTERFERON α2 (IFNα2) MUTANTS
SG155183A1 (en) * 2005-08-26 2009-09-30 Ares Trading Sa Process for the preparation of glycosylated interferon beta
WO2007049940A1 (en) * 2005-10-27 2007-05-03 Peptron Co., Ltd Bioactive substance-blood protein conjugate and stabilization of a bioactive substance using the same
US20080280328A1 (en) * 2005-11-18 2008-11-13 Novozymes A/S Glucoamylase Variants
AU2006323925B2 (en) * 2005-12-09 2012-08-02 Ares Trading S.A. Method for purifying FSH or a FSH mutant
US8841255B2 (en) 2005-12-20 2014-09-23 Duke University Therapeutic agents comprising fusions of vasoactive intestinal peptide and elastic peptides
US20130172274A1 (en) 2005-12-20 2013-07-04 Duke University Methods and compositions for delivering active agents with enhanced pharmacological properties
EP1971355B1 (en) 2005-12-20 2020-03-11 Duke University Methods and compositions for delivering active agents with enhanced pharmacological properties
JP2009520469A (ja) * 2005-12-22 2009-05-28 コンジュクヘム ビオテクフノロギエス インコーポレイテッド アルブミンと治療薬との前もって形成された抱合体の産生のための方法
US10221228B2 (en) 2006-02-03 2019-03-05 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US8304386B2 (en) * 2006-02-03 2012-11-06 Prolor Biotech, Inc. Long-acting growth hormone and methods of producing same
US7553940B2 (en) 2006-02-03 2009-06-30 Modigene Inc Long-acting EPO polypeptides and derivatives thereof and methods thereof
US10351615B2 (en) 2006-02-03 2019-07-16 Opko Biologics Ltd. Methods of treatment with long-acting growth hormone
US9458444B2 (en) 2006-02-03 2016-10-04 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
US9249407B2 (en) 2006-02-03 2016-02-02 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
US8048848B2 (en) * 2006-02-03 2011-11-01 Prolor Biotech Ltd. Long-acting interferons and derivatives thereof and methods thereof
US20150038413A1 (en) 2006-02-03 2015-02-05 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US20140113860A1 (en) 2006-02-03 2014-04-24 Prolor Biotech Ltd. Long-acting polypeptides and methods of producing and administering same
US8476234B2 (en) * 2006-02-03 2013-07-02 Prolor Biotech Inc. Long-acting coagulation factors and methods of producing same
US8759292B2 (en) 2006-02-03 2014-06-24 Prolor Biotech, Llc Long-acting coagulation factors and methods of producing same
US8946155B2 (en) 2006-02-03 2015-02-03 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US8450269B2 (en) 2006-02-03 2013-05-28 Prolor Biotech Ltd. Long-acting growth hormone and methods of producing same
US8048849B2 (en) 2006-02-03 2011-11-01 Modigene, Inc. Long-acting polypeptides and methods of producing same
US20080261893A1 (en) * 2006-02-24 2008-10-23 Denise Barbut Topical corneal analgesia using neurotensin receptor agonists and synergistic neurotensin combinations without delaying wound healing
ES2683919T3 (es) 2006-04-24 2018-09-28 Medical Instill Technologies, Inc. Dispositivo de liofilización que puede perforarse con una aguja y volverse a sellar, y método relacionado
ES2351527T3 (es) 2006-05-30 2011-02-07 Intarcia Therapeutics, Inc Modulador de flujo en dos piezas con conducto interno para un sistema osmótico de administración.
EP2359808B1 (en) 2006-08-09 2013-05-22 Intarcia Therapeutics, Inc Osmotic delivery systems and piston assemblies
TWI430806B (zh) * 2006-09-13 2014-03-21 Smithkline Beecham Corp 用於投與長效降血糖藥劑之方法
ATE495239T1 (de) * 2007-03-09 2011-01-15 Vectorlogics Inc Zellen für adenovirusvektor- und proteinherstellung
EP2131651B1 (en) * 2007-03-12 2013-05-22 Sarentis Therapeutics, Inc. Topical corneal analgesia using neurotensin receptor agonists
EP2157967B1 (en) 2007-04-23 2013-01-16 Intarcia Therapeutics, Inc Suspension formulations of insulinotropic peptides and uses thereof
EP2076533B1 (en) * 2007-05-02 2014-10-08 Ambrx, Inc. Modified interferon beta polypeptides and their uses
US20100256337A1 (en) * 2007-10-22 2010-10-07 Merck Serono Sa Method for purifying an fc-containing protein
JP2011500756A (ja) * 2007-10-22 2011-01-06 メルク セローノ ソシエテ アノニム Ｆｃ融合タンパク質を精製する方法
US20090186819A1 (en) * 2007-12-11 2009-07-23 Marieve Carrier Formulation of insulinotropic peptide conjugates
US20100297081A1 (en) * 2007-12-18 2010-11-25 Huang Yanshan Pharmaceutical formulation containing recombinant human serum albumin-interferon alpha fusion protein
CA2726861C (en) 2008-02-13 2014-05-27 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US8476408B2 (en) * 2008-06-13 2013-07-02 Alize Pharma Sas Unacylated ghrelin and analogs as therapeutic agents for vascular remodeling in diabetic patients and treatment of cardiovascular disease
WO2009158704A2 (en) 2008-06-27 2009-12-30 Duke University Therapeutic agents comprising elastin-like peptides
US20110171219A1 (en) * 2008-09-19 2011-07-14 Fahar Merchant Treating cancer stem cells using targeted cargo proteins
EP2353010B1 (en) 2008-10-28 2015-07-08 Uladzimir A. Murauski Methods for detection of toxemia
EP2344519B1 (en) * 2008-11-07 2016-09-28 The General Hospital Corporation C-terminal fragments of glucagon-like peptide-1 (glp-1)
WO2010056732A1 (en) 2008-11-12 2010-05-20 Marv Enterprises Llc Utilization of stents for the treatment of blood borne carcinomas
BRPI0921586A2 (pt) 2008-11-18 2019-09-24 Merrimack Pharmaceuticals Inc articuladores de albumina de soro humana e conjugados destes
PT2373681T (pt) * 2008-12-10 2017-04-11 Glaxosmithkline Llc Composições farmacêuticas de albiglutida
AU2014202190B2 (en) * 2009-01-16 2016-03-17 Teva Pharmaceutical Industries Ltd. New Stable Formulations of Recombinant Human Albumin-Human Granulocyte Colony Stimulating Factor Fusion Protein
WO2010081494A1 (en) * 2009-01-19 2010-07-22 King Faisal Specialist Hospital And Research Centre A method of increasing protein expression in eukaryotic cells
WO2010087994A2 (en) 2009-01-30 2010-08-05 Whitehead Institute For Biomedical Research Methods for ligation and uses thereof
WO2010096394A2 (en) 2009-02-17 2010-08-26 Redwood Biosciences, Inc. Aldehyde-tagged protein-based drug carriers and methods of use
US9216386B2 (en) * 2009-03-17 2015-12-22 Marv Enterprises, LLC Sequential extracorporeal treatment of bodily fluids
US9403898B2 (en) 2009-05-07 2016-08-02 Novozymes Biopharma Dk A/S Method for purifying albumin
US9663778B2 (en) 2009-07-09 2017-05-30 OPKO Biologies Ltd. Long-acting coagulation factors and methods of producing same
EP2464370B1 (en) 2009-08-14 2017-03-29 Phasebio Pharmaceuticals, Inc. Modified vasoactive intestinal peptides
CN101993485B (zh) 2009-08-20 2013-04-17 重庆富进生物医药有限公司 促胰岛素分泌肽类似物同源二聚体及其用途
AU2010290131C1 (en) 2009-08-24 2015-12-03 Amunix Operating Inc. Coagulation factor VII compositions and methods of making and using same
US8451450B2 (en) * 2009-09-14 2013-05-28 Bio-Rad Laboratories, Inc. Near real time optical phase conjugation
EP3323423B1 (en) 2009-09-28 2020-06-17 Intarcia Therapeutics, Inc Rapid establishment and/or termination of substantial steady-state drug delivery
WO2011053545A1 (en) * 2009-10-30 2011-05-05 Merck Sharp & Dohme Corp. Granulocyte-colony stimulating factor produced in glycoengineered pichia pastoris
CA2782424C (en) 2009-12-06 2021-07-27 Biogen Idec Hemophilia Inc. Factor viii-fc chimeric and hybrid polypeptides, and methods of use thereof
WO2011140176A1 (en) 2010-05-04 2011-11-10 Glaxosmithkline Llc Methods for treating or preventing cardiovascular disorders and providing cardiovascular protection
EA201291482A1 (ru) 2010-07-09 2013-10-30 Байоджен Айдек Хемофилия Инк. Химерные факторы коагуляции
CN103140237A (zh) 2010-07-09 2013-06-05 比奥根艾迪克依蒙菲利亚公司 因子ix多肽及其使用方法
WO2012012271A2 (en) * 2010-07-19 2012-01-26 Sialix, Inc. Novel glycosylated polypeptides
ES2630031T3 (es) 2010-09-28 2017-08-17 Aegerion Pharmaceuticals, Inc. Un polipéptido de leptina pinnípedo-humano quimérico con solubilidad aumentada
US8892184B2 (en) 2010-10-18 2014-11-18 Siemens Medical Solutions Usa, Inc. Systems and methods for reducing interference in a dual modality imaging system
CN102453095A (zh) * 2010-11-01 2012-05-16 天津药物研究院 含有glp-1的融合蛋白、制备方法及其应用
AU2011350066A1 (en) 2010-12-27 2013-07-11 Alexion Pharma International Sarl Compositions comprising natriuretic peptides and methods of use thereof
JP6162606B2 (ja) 2011-01-14 2017-07-12 レッドウッド バイオサイエンス， インコーポレイテッド アルデヒド−タグ付き免疫グロブリンポリペプチド及びその使用方法
CN107837395A (zh) * 2011-02-09 2018-03-27 葛兰素史密斯克莱有限责任公司 冻干制剂
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
WO2012118323A2 (ko) * 2011-02-28 2012-09-07 고려대학교 산학협력단 알부민과 레티놀 결합 단백질의 융합 단백질
US9701732B2 (en) 2011-02-28 2017-07-11 Korea University Research And Business Foundation Fusion protein comprising albumin and retinol-binding protein
US10064915B2 (en) 2011-02-28 2018-09-04 Korea University Research And Business Foundation Fusion protein comprising albumin and retinol-binding protein
US9089312B2 (en) 2011-03-10 2015-07-28 Western New England University Tamponade for biopsy surgery and method of operation
US9205131B2 (en) * 2011-03-30 2015-12-08 The Regents Of The University Of California Use of IL-17D for the treatment and prevention of cancers
US8558546B2 (en) * 2011-04-13 2013-10-15 Mark Griswold Relaxometry
EP2709648A4 (en) 2011-05-19 2015-04-08 Geysen Hendrik M COMPOUNDS FOR BINDING TO THE ERYTHROPOIETIN RECEPTOR
CA2873553C (en) 2011-06-06 2020-01-28 Phasebio Pharmaceuticals, Inc. Use of modified vasoactive intestinal peptides in the treatment of hypertension
SI2717898T1 (sl) 2011-06-10 2019-07-31 Bioverativ Therapeutics Inc. Spojine prokoagulantov in metode za njihovo uporabo
JP6005736B2 (ja) * 2011-06-13 2016-10-12 ニューメディシンズ，インコーポレーテッド Ｉｌ−１２を用いる皮膚損傷の軽減
WO2013003555A1 (en) 2011-06-28 2013-01-03 Whitehead Institute For Biomedical Research Using sortases to install click chemistry handles for protein ligation
WO2013006692A2 (en) 2011-07-06 2013-01-10 The General Hospital Corporation Methods of treatment using a pentapeptide derived from the c-terminus of glucagon-like peptide 1 (glp-1)
ES2722209T3 (es) 2011-07-08 2019-08-08 Bioverativ Therapeutics Inc Polipéptidos quiméricos e híbridos del Factor VIII, y métodos de uso de los mismos
JP6006309B2 (ja) * 2011-07-08 2016-10-12 アミリン・ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニーＡｍｙｌｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｌｌｃ 作用持続期間が増大し、免疫原性が減少した操作されたポリペプチド
WO2013016454A1 (en) 2011-07-25 2013-01-31 Biogen Idec Hemophilia Inc. Assays to monitor bleeding disorders
CN103998470A (zh) 2011-08-17 2014-08-20 科罗拉多大学董事会法人团体 运铁蛋白-肿瘤抑素融合蛋白质及其生成和使用方法
WO2013028451A1 (en) * 2011-08-19 2013-02-28 Marv Enterprises Method for the treatment of cancer
WO2013056079A1 (en) * 2011-10-13 2013-04-18 The Johns Hopkins University High affinity beta lactamase inhibitors
JP2015509091A (ja) 2012-01-09 2015-03-26 ザ スクリプス リサーチ インスティテュート ヒト化抗体
CA2863224A1 (en) 2012-01-09 2013-07-18 The Scripps Research Institute Ultralong complementarity determining regions and uses thereof
CA2863328A1 (en) 2012-01-12 2013-07-18 Biogen Idec Ma Inc. Chimeric factor viii polypeptides and uses thereof
CA2864126A1 (en) 2012-02-15 2013-08-22 Biogen Idec Ma Inc. Recombinant factor viii proteins
SI3564260T1 (sl) 2012-02-15 2023-02-28 Bioverativ Therapeutics Inc. Sestavki faktorja VIII in postopki njegove izdelave in uporabe
EP2817626B1 (en) 2012-02-20 2017-09-27 Uladzimir A. Murauski Methods for detection of active malignancy
US20150027950A1 (en) * 2012-03-27 2015-01-29 Marv Enterprises, LLC Treatment for atherosclerosis
EP2830646B1 (en) 2012-03-27 2018-03-07 NGM Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2013151649A1 (en) 2012-04-04 2013-10-10 Sialix Inc Glycan-interacting compounds
PE20142405A1 (es) 2012-04-19 2015-01-25 Opko Biolog Ltd Variantes de oxintomodulina de accion prolongada y metodos de produccion de las mismas
AU2013263349B2 (en) 2012-05-17 2016-09-08 Extend Biosciences, Inc Carriers for improved drug delivery
WO2013170636A1 (zh) * 2012-05-18 2013-11-21 爱德迪安（北京）生物技术有限公司 用于糖尿病治疗的蛋白、蛋白缀合物及其应用
US10052366B2 (en) 2012-05-21 2018-08-21 Alexion Pharmaceuticsl, Inc. Compositions comprising alkaline phosphatase and/or natriuretic peptide and methods of use thereof
AU2013270683A1 (en) 2012-06-08 2014-12-11 Biogen Ma Inc. Chimeric clotting factors
EP3693000B1 (en) 2012-06-08 2022-03-02 Bioverativ Therapeutics Inc. Procoagulant compounds
EP2870250B2 (en) 2012-07-06 2022-06-29 Bioverativ Therapeutics Inc. Cell line expressing single chain factor viii polypeptides and uses thereof
EA029685B1 (ru) 2012-07-11 2018-04-30 Амуникс Оперэйтинг Инк. Комплекс фактора viii с xten и белком фактора фон виллебранда и его применение (варианты)
CN102816244A (zh) * 2012-08-23 2012-12-12 无锡和邦生物科技有限公司 一种Exendin-4肽与人血清白蛋白HSA的融合蛋白及其制备方法
US20150252345A1 (en) 2012-09-25 2015-09-10 Biogen Idec Ma Inc. Methods of Using FIX Polypeptides
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
CA2888806A1 (en) 2012-10-18 2014-04-24 Biogen Idec Ma Inc. Methods of using a fixed dose of a clotting factor
EP3943102A1 (en) 2012-10-30 2022-01-26 Bioverativ Therapeutics Inc. Methods of using fviii polypeptide
SG10202010383YA (en) 2012-11-20 2020-11-27 Opko Biologics Ltd Method of increasing the hydrodynamic volume of polypeptides by attaching to gonadotrophin carboxy terminal peptides
JP2016503771A (ja) 2012-12-21 2016-02-08 サノフイ エキセンジン−４誘導体
CN105073781A (zh) * 2013-01-11 2015-11-18 加州生物医学研究所 牛融合抗体
CA2896793A1 (en) 2013-01-15 2014-07-24 Teva Pharmaceutical Industries Ltd. Formulations of albu-bche, preparation and uses thereof
WO2014120619A2 (en) 2013-01-30 2014-08-07 Ngm Biopharmaceuticals, Inc. Compositions and methods of use in treating metabolic disorders
US9161966B2 (en) 2013-01-30 2015-10-20 Ngm Biopharmaceuticals, Inc. GDF15 mutein polypeptides
HRP20231183T1 (hr) 2013-02-15 2024-01-05 Bioverativ Therapeutics Inc. Optimizirani gen faktora viii
CA2903739A1 (en) * 2013-03-06 2014-09-12 Glaxosmithkline Llc Host cells and methods of use
ES2853935T3 (es) 2013-03-12 2021-09-20 Massachusetts Gen Hospital Proteínas modificadas de sustancia inhibidora muleriana (MIS) y usos de las mismas para el tratamiento de enfermedades
TWI629993B (zh) 2013-03-15 2018-07-21 美商生物化學醫療公司 因子ｖｉｉｉ多肽調配物
TWI788044B (zh) 2013-03-15 2022-12-21 美商百歐維拉提夫治療公司 因子ｉｘ多肽調配物
WO2014147489A2 (en) 2013-03-15 2014-09-25 Teva Pharmaceutical Industries Ltd. Recombinant human albumin-human granulocyte colony stimulating factor for the prevention of neutropenia in pediatric patients
US9849066B2 (en) 2013-04-24 2017-12-26 Corning Incorporated Delamination resistant pharmaceutical glass containers containing active pharmaceutical ingredients
SG11201509201WA (en) * 2013-05-06 2015-12-30 Cell Machines Inc Methods and compositions related to large scale production of proteins
EA201592022A1 (ru) 2013-06-28 2016-05-31 Байоджен Ма Инк. Расщепляемый тромбином линкер, содержащий xten, и его применение
EP3022221B1 (en) 2013-07-18 2021-09-15 Taurus Biosciences, LLC Humanized antibodies with ultralong complementarity determining regions
EP3033097B1 (en) 2013-08-14 2021-03-10 Bioverativ Therapeutics Inc. Factor viii-xten fusions and uses thereof
EP4108254A1 (en) 2013-08-14 2022-12-28 Bioverativ Therapeutics Inc. Recombinant factor viii proteins
US10258668B2 (en) 2013-09-20 2019-04-16 The General Hospital Corporation Viral vectors for expressing a modified mullerian inhibiting substance (MIS) protein
WO2015048330A2 (en) 2013-09-25 2015-04-02 Biogen Idec Ma Inc. On-column viral inactivation methods
CN103554266B (zh) * 2013-10-11 2015-05-27 哈尔滨医科大学 一种具有抗肿瘤作用的肿瘤抑素融合肽及其制备方法和应用
US20150158926A1 (en) 2013-10-21 2015-06-11 Opko Biologics, Ltd. Long-acting polypeptides and methods of producing and administering same
CN103656618B (zh) * 2013-10-25 2016-06-08 广东药学院 治疗皮肤创伤的多肽纳米纤维凝胶制剂、制备方法及应用
WO2015070014A1 (en) 2013-11-08 2015-05-14 Biogen Idec Ma Inc. Procoagulant fusion compound
ES2967617T3 (es) 2013-12-06 2024-05-03 Bioverativ Therapeutics Inc Herramientas de farmacocinética poblacional y sus usos
AU2014362307A1 (en) 2013-12-11 2016-06-30 The General Hospital Corporation Use of mullerian inhibiting substance (MIS) proteins for contraception and ovarian reserve preservation
EP3080149A1 (en) 2013-12-13 2016-10-19 Sanofi Dual glp-1/glucagon receptor agonists
EP3080154B1 (en) 2013-12-13 2018-02-07 Sanofi Dual glp-1/gip receptor agonists
EP3080150B1 (en) 2013-12-13 2018-08-01 Sanofi Exendin-4 peptide analogues as dual glp-1/gip receptor agonists
WO2015086730A1 (en) 2013-12-13 2015-06-18 Sanofi Non-acylated exendin-4 peptide analogues
CN114736305B (zh) 2014-01-10 2023-05-05 比奥贝拉蒂治疗公司 因子viii嵌合蛋白及其用途
AU2015236340B2 (en) 2014-03-24 2020-02-06 Bioverativ Therapeutics Inc. Lyophilized factor IX formulations
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
US20150316566A1 (en) 2014-05-02 2015-11-05 Cerenis Therapeutics Holding Sa Hdl therapy markers
EP3139949B1 (en) 2014-05-08 2020-07-29 Phasebio Pharmaceuticals, Inc. Compositions comprising a vip-elp fusion protein for use in treating cystic fibrosis
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
WO2016004113A1 (en) 2014-06-30 2016-01-07 Biogen Ma Inc. Optimized factor ix gene
WO2016007873A1 (en) 2014-07-11 2016-01-14 The Regents Of The University Of Michigan Compositions and methods for treating craniosynostosis
CN106573966B (zh) 2014-07-30 2022-03-01 Ngm生物制药有限公司 用于治疗代谢异常的组合物和方法
US9616114B1 (en) 2014-09-18 2017-04-11 David Gordon Bermudes Modified bacteria having improved pharmacokinetics and tumor colonization enhancing antitumor activity
AP2017009826A0 (en) 2014-09-26 2017-03-31 Bayer Pharma AG Stabilized adrenomedullin derivatives and use thereof
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
AU2015327900B2 (en) * 2014-10-03 2020-04-30 Ngm Biopharmaceuticals, Inc. Methods and compositions for treatment of conditions associated with elevated triglycerides
PL3207130T3 (pl) 2014-10-14 2020-02-28 Halozyme, Inc. Kompozycje deaminazy adenozyny 2 (ada2), jej warianty i sposoby ich zastosowania
US9789197B2 (en) 2014-10-22 2017-10-17 Extend Biosciences, Inc. RNAi vitamin D conjugates
CA2964463C (en) 2014-10-22 2024-02-13 Extend Biosciences, Inc. Therapeutic vitamin d conjugates
WO2016065052A1 (en) 2014-10-22 2016-04-28 Extend Biosciences, Inc. Insulin vitamin d conjugates
MA40835A (fr) 2014-10-23 2017-08-29 Biogen Ma Inc Anticorps anti-gpiib/iiia et leurs utilisations
MA40861A (fr) 2014-10-31 2017-09-05 Biogen Ma Inc Anticorps anti-glycoprotéines iib/iiia
MD20170035A2 (ro) 2014-10-31 2017-09-30 Ngm Biopharmaceuticals Inc Compoziţii şi metode de utilizare pentru tratamentul tulburărilor metabolice
US9879087B2 (en) 2014-11-12 2018-01-30 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
SI3218005T1 (sl) 2014-11-12 2023-06-30 Seagen Inc. Z glikanom delujoče spojine, in postopki uporabe
JP6787894B2 (ja) 2014-12-05 2020-11-18 アレクシオン ファーマシューティカルズ， インコーポレイテッド 組換えアルカリホスファターゼを用いた発作の処置
JP6868561B2 (ja) 2015-01-28 2021-05-12 アレクシオン ファーマシューティカルズ， インコーポレイテッド アルカリホスファターゼ欠損を有する被験者を治療する方法
CA2976038A1 (en) 2015-02-09 2016-08-18 Phasebio Pharmaceuticals, Inc. Methods and compositions for treating muscle disease and disorders
MA44390A (fr) 2015-06-03 2019-01-23 Intarcia Therapeutics Inc Systèmes de mise en place et de retrait d'implant
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
CN108289851B (zh) 2015-06-19 2021-06-01 Opko生物科学有限公司 长效凝固因子及其产生方法
AR105284A1 (es) 2015-07-10 2017-09-20 Sanofi Sa Derivados de exendina-4 como agonistas peptídicos duales específicos de los receptores de glp-1 / glucagón
CN108472337B (zh) 2015-08-03 2022-11-25 比奥贝拉蒂治疗公司 因子ix融合蛋白以及其制备和使用方法
US11352612B2 (en) 2015-08-17 2022-06-07 Alexion Pharmaceuticals, Inc. Manufacturing of alkaline phosphatases
EP3349730B1 (en) 2015-09-18 2020-12-02 Dnarx Systems for nucleic acid expression in vivo
EP3355904A4 (en) 2015-09-28 2019-06-12 Alexion Pharmaceuticals, Inc. IDENTIFICATION OF EFFECTIVE DOSE SHEETS FOR TISSUE-SPECIFIC ALKALINE PHOSPHATASE ENZYMERSAT THERAPY OF HYPOPHOSPHATASIA
CN106589130B (zh) * 2015-10-14 2019-11-01 阿思科力(苏州)生物科技有限公司 一种Slit2D2-HSA重组蛋白及其在治疗脓毒症中的应用
JP6920293B2 (ja) * 2015-10-30 2021-08-18 メドイミューン・リミテッドＭｅｄＩｍｍｕｎｅ Ｌｉｍｉｔｅｄ ＩｇＧ軽鎖におけるＮ末端切断の防止
US11400140B2 (en) 2015-10-30 2022-08-02 Alexion Pharmaceuticals, Inc. Methods for treating craniosynostosis in a patient
CA3002097A1 (en) 2015-11-12 2017-05-18 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
HRP20221089T1 (hr) 2016-02-01 2022-11-25 Bioverativ Therapeutics Inc. Optimizirani geni faktora viii
WO2017155569A1 (en) 2016-03-08 2017-09-14 Alexion Pharmaceuticals, Inc. Methods for treating hypophosphatasia in children
TWI815793B (zh) 2016-03-31 2023-09-21 美商恩格姆生物製藥公司 結合蛋白質及其使用方法
EP3436020A4 (en) 2016-04-01 2019-12-25 Alexion Pharmaceuticals, Inc. METHOD FOR TREATING HYPOPHOSPHATASIE IN TEENS AND ADULTS
JP2019513711A (ja) 2016-04-01 2019-05-30 アレクシオン ファーマシューティカルズ， インコーポレイテッド アルカリホスファターゼによって筋力低下を治療すること
JP2019515677A (ja) 2016-04-26 2019-06-13 アール．ピー．シェーラー テクノロジーズ エルエルシー 抗体複合体ならびにそれを作製および使用する方法
EP3452021B1 (en) 2016-05-06 2021-12-29 Phasebio Pharmaceuticals, Inc. Elp fusion proteins for controlled and sustained release
SG11201810102SA (en) 2016-05-16 2018-12-28 Intarcia Therapeutics Inc Glucagon-receptor selective polypeptides and methods of use thereof
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
WO2017214130A1 (en) 2016-06-06 2017-12-14 Alexion Pharmaceuticals, Inc. Metal impact on manufacturing of alkaline phosphatases
KR20240006077A (ko) 2016-07-11 2024-01-12 옵코 바이오로직스 리미티드 지속성 응고 인자 vii 및 그 제조 방법
WO2018026742A1 (en) * 2016-08-01 2018-02-08 Askgene Pharma Inc. Novel antibody-albumin-drug conjugates (aadc) and methods for using them
US11116821B2 (en) 2016-08-18 2021-09-14 Alexion Pharmaceuticals, Inc. Methods for treating tracheobronchomalacia
EP3541847A4 (en) 2016-11-17 2020-07-08 Seattle Genetics, Inc. COMPOUNDS INTERACTING WITH GLYCANE AND METHODS OF USE
IL308416A (en) 2016-12-02 2024-01-01 Bioverativ Therapeutics Inc Methods for the treatment of hemophilic arthritis with the help of chimeric blood coagulation factors
KR20190091292A (ko) 2016-12-02 2019-08-05 바이오버라티브 테라퓨틱스 인크. 응고 인자에 대한 면역 내성 유도 방법
US11180535B1 (en) 2016-12-07 2021-11-23 David Gordon Bermudes Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria
US11129906B1 (en) 2016-12-07 2021-09-28 David Gordon Bermudes Chimeric protein toxins for expression by therapeutic bacteria
AU2017376400A1 (en) * 2016-12-13 2019-06-20 Novozymes A/S Methods for treating inflammatory conditions of the lungs
WO2018112168A1 (en) 2016-12-14 2018-06-21 The General Hospital Corporation Mullerian inhibiting substance (mis) proteins for ovarian and uterine oncoprotection, and ovarian reserve and uterine preservation
WO2018112362A1 (en) 2016-12-16 2018-06-21 Biogen Ma Inc. Stabilized proteolytically activated growth differentiation factor 11
CN110225762A (zh) 2017-01-03 2019-09-10 因塔西亚制药公司 包括glp-1受体激动剂的连续施用和药物的共同施用的方法
BR112019015569A2 (pt) 2017-01-31 2020-03-17 Bioverativ Therapeutics Inc. Proteínas de fusão do fator ix e métodos para a sua produção e uso
WO2018156602A1 (en) * 2017-02-21 2018-08-30 The Regents Of The University Of Michigan Il-22bp compositions and method for the treatment of disease therewith
MX2019010202A (es) 2017-03-03 2019-10-02 Seattle Genetics Inc Compuestos que interactuan con glicano y metodos de uso.
CN116392609A (zh) 2017-03-23 2023-07-07 Dnarx公司 用于体内核酸表达的系统和方法
US10767164B2 (en) 2017-03-30 2020-09-08 The Research Foundation For The State University Of New York Microenvironments for self-assembly of islet organoids from stem cells differentiation
AU2018243320A1 (en) 2017-03-31 2019-10-10 Alexion Pharmaceuticals, Inc. Methods for treating hypophosphatasia (HPP) in adults and adolescents
WO2018213766A1 (en) * 2017-05-19 2018-11-22 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods for improving cognition
SG11202000764RA (en) 2017-08-09 2020-02-27 Bioverativ Therapeutics Inc Nucleic acid molecules and uses thereof
CA3073317A1 (en) 2017-08-18 2019-02-21 Neutrolis Therapeutics, Inc. Engineered dnase enzymes and use in therapy
US20220315919A1 (en) * 2017-10-27 2022-10-06 Svar Life Science Ab Secreted Reporter-Peptides for Optimizing Cell-Based Assays for Analysis on Immuno-Assay Platforms
JP7291694B2 (ja) 2017-11-10 2023-06-15 エヌジーエム バイオファーマシューティカルス，インコーポレーテッド Ａｎｇｐｔｌ８結合薬及びその使用方法
BR112020015228A2 (pt) 2018-02-01 2020-12-29 Bioverativ Therapeutics Inc. Uso de vetores lentivirais que expressam fator viii
AU2019244091B2 (en) 2018-03-28 2023-12-07 Bristol-Myers Squibb Company Interleukin-2/Interleukin-2 receptor alpha fusion proteins and methods of use
WO2019190752A1 (en) 2018-03-30 2019-10-03 Alexion Pharmaceuticals, Inc. Manufacturing of glycoproteins
EP3794024B1 (en) 2018-05-14 2023-05-10 Werewolf Therapeutics, Inc. Activatable interleukin-2 polypeptides and methods of use thereof
BR112020023167A2 (pt) 2018-05-14 2021-02-09 Werewolf Therapeutics, Inc. polipeptídeos de citocina ativáveis e métodos de uso destes
JP2021523878A (ja) 2018-05-18 2021-09-09 バイオベラティブ セラピューティクス インコーポレイテッド 血友病ａを処置する方法
EP3817720A2 (en) 2018-07-03 2021-05-12 Bristol-Myers Squibb Company Fgf21 formulations
KR20200135618A (ko) 2019-05-23 2020-12-03 ㈜ 디앤디파마텍 폴리펩티드를 포함하는 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물
EP3823659A4 (en) 2018-07-19 2022-06-22 D&D Pharmatech Inc. PHARMACEUTICAL COMPOSITION WITH A POLYPEPTIDE
JP2021533753A (ja) 2018-08-09 2021-12-09 バイオベラティブ セラピューティクス インコーポレイテッド 核酸分子及び非ウイルス遺伝子治療のためのそれらの使用
WO2020056242A1 (en) * 2018-09-14 2020-03-19 Billion Bottle Project Ultraviolet (uv) dosimetry
AU2019357621A1 (en) 2018-10-11 2021-05-27 Intarcia Therapeutics, Inc. Human amylin analog polypeptides and methods of use
CN109762069B (zh) * 2018-11-05 2022-01-14 广州领晟医疗科技有限公司 一种融合蛋白、其药物组合物及用途
US20220119494A1 (en) * 2018-11-14 2022-04-21 Sudershan Biotech Pvt Ltd Recombinant vector, host cell and process for production of human serum albumin
CA3121786A1 (en) 2018-12-06 2020-06-11 Bioverativ Therapeutics Inc. Use of lentiviral vectors expressing factor ix
CN109627343A (zh) * 2018-12-27 2019-04-16 北京美福源生物医药科技有限公司 长效细胞因子基因衍生物融合蛋白
WO2020160118A1 (en) 2019-01-29 2020-08-06 Shire-Nps Pharmaceuticals, Inc. Parathyroid hormone variants
CN114450022A (zh) 2019-05-14 2022-05-06 狼人治疗公司 分离部分及其使用方法
CN114174326A (zh) 2019-06-18 2022-03-11 拜耳公司 长期稳定的肾上腺髓质素类似物及其用途
EP4038182A1 (en) 2019-09-30 2022-08-10 Bioverativ Therapeutics Inc. Lentiviral vector formulations
US20240158458A1 (en) * 2019-10-15 2024-05-16 Moderna TX, Inc. Mrnas encoding immune modulating polypeptides and uses thereof
US20240132566A1 (en) 2019-10-16 2024-04-25 Jcr Pharmaceuticals Co., Ltd. Method for producing fusion protein of serum albumin and growth hormone
EP4059512A4 (en) 2019-10-30 2023-12-06 JCR Pharmaceuticals Co., Ltd. AQUEOUS PHARMACEUTICAL COMPOSITION CONTAINING SERUM ALBUMIN FUSION PROTEIN AND GROWTH HORMONE
EP4137507A4 (en) * 2020-04-14 2024-04-24 Senelix Co Ltd RECOMBINANT FUSION PROTEIN FOR THE PREVENTION OR TREATMENT OF FIBROTIC DISEASES
EP4192495A1 (en) 2020-08-07 2023-06-14 Bristol-Myers Squibb Company Fgf21 combined with ccr2/5 antagonists for the treatment of fibrosis
CN112724259B (zh) * 2020-11-16 2022-12-20 天津林达生物科技有限公司 人血清白蛋白与白介素2的融合蛋白及其用途
US20240123031A1 (en) 2020-11-25 2024-04-18 Bristol-Myers Squibb Company Methods of treating liver diseases
WO2022159414A1 (en) 2021-01-22 2022-07-28 University Of Rochester Erythropoietin for gastroinfestinal dysfunction
CN112915106A (zh) * 2021-02-05 2021-06-08 张虎山 一种肿瘤免疫微环境调控剂的制备及其应用
CN114539426B (zh) * 2022-03-02 2023-07-07 山东仙普爱瑞科技股份有限公司 一种含干扰素α的融合蛋白、表达该融合蛋白的重组菌株及其制备方法

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
EP0058481A1 (en) 1981-02-16 1982-08-25 Zeneca Limited Continuous release pharmaceutical compositions
EP0133988A2 (de) 1983-08-02 1985-03-13 Hoechst Aktiengesellschaft Regulatorische Peptide enthaltende pharmazeutische Präparate mit protrahierter Freisetzung und Verfahren zu deren Herstellung
EP0251744A2 (en) 1986-06-27 1988-01-07 Delta Biotechnology Limited Process for the genetic modification of yeast
EP0258067A2 (en) 1986-08-29 1988-03-02 Delta Biotechnology Limited Yeast promoter
EP0322094A1 (en) 1987-10-30 1989-06-28 Delta Biotechnology Limited N-terminal fragments of human serum albumin
EP0330451A2 (en) 1988-02-22 1989-08-30 Toa Nenryo Kogyo Kabushiki Kaisha A cDNA coding for human normal serum albumin a, and a process for production of the albumin
WO1990001063A1 (en) 1988-07-23 1990-02-08 Delta Biotechnology Limited New secretory leader sequences
EP0361991A2 (en) 1988-08-05 1990-04-04 Rhone-Poulenc Sante Method for the microbiological preparation of human serum albumin and other heterologous proteins from a yeast
JPH0336516B2 (ja) 1985-10-21 1991-05-31 Kogyo Gijutsuin
WO1997033899A1 (en) 1996-03-14 1997-09-18 Human Genome Sciences, Inc. Apoptosis inducing molecule i
WO1997034911A1 (en) 1996-03-22 1997-09-25 Human Genome Sciences, Inc. Apoptosis inducing molecule ii
WO1998030213A2 (en) 1997-01-08 1998-07-16 Paracelsian, Inc. Use of the ah receptor and ah receptor ligands to treat or prevent the cytopathicity of viral infection
WO1998050347A1 (en) 1997-05-05 1998-11-12 The Regents Of The University Of California Naphthols useful in antiviral methods
WO1998054366A1 (en) 1997-06-02 1998-12-03 Subsidiary No. 3, Inc. Compositions and methods for inhibiting human immunodeficiency virus infection by down-regulating human cellular genes
WO1999023105A1 (en) 1997-11-03 1999-05-14 Human Genome Sciences, Inc. Vegi, an inhibitor of angiogenesis and tumor growth
WO1999049830A2 (de) 1998-03-27 1999-10-07 Retro-Tech Gmbh Anti-virale wirkung von propolis durch inhibition viraler nukleinsäure polymerasen
WO1999056764A1 (en) 1998-04-30 1999-11-11 Teijin Limited Method for preventing or treating a human immunodeficiency virus infection
WO1999066936A1 (en) 1998-06-24 1999-12-29 Emory University Use of 3'-azido-2',3'-dideoxyuridine in combination with further anti-hiv drugs for the manufacture of a medicament for the treatment of hiv
WO2000069911A1 (en) 1999-05-17 2000-11-23 Conjuchem, Inc. Long lasting insulinotropic peptides
WO2001079258A1 (en) 2000-04-12 2001-10-25 Human Genome Sciences, Inc. Albumin fusion proteins

Family Cites Families (622)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1172046A (en) * 1915-07-30 1916-02-15 Henry Psencik Plow.
US5625041A (en) * 1990-09-12 1997-04-29 Delta Biotechnology Limited Purification of proteins
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
DE2449885C3 (de) 1974-10-21 1980-04-30 Biotest-Serum-Institut Gmbh, 6000 Frankfurt Verfahren zur Herstellung von chemisch modifizierten haltbaren Hämoglobinpräparaten sowie das nach diesem Verfahren hergestellte modifizierte Hämoglobinpräparat
US4002531A (en) 1976-01-22 1977-01-11 Pierce Chemical Company Modifying enzymes with polyethylene glycol and product produced thereby
US4363877B1 (en) 1977-09-23 1998-05-26 Univ California Recombinant dna transfer vectors
US4264731A (en) 1977-05-27 1981-04-28 The Regents Of The University Of California DNA Joining method
US4440859A (en) 1977-05-27 1984-04-03 The Regents Of The University Of California Method for producing recombinant bacterial plasmids containing the coding sequences of higher organisms
US4407948A (en) 1977-09-23 1983-10-04 The Regents Of The University Of California Purification of nucleotide sequences suitable for expression in bacteria
US4283489A (en) 1977-09-23 1981-08-11 The Regents Of The University Of California Purification of nucleotide sequences suitable for expression in bacteria
US4366246A (en) 1977-11-08 1982-12-28 Genentech, Inc. Method for microbial polypeptide expression
US4263428A (en) 1978-03-24 1981-04-21 The Regents Of The University Of California Bis-anthracycline nucleic acid function inhibitors and improved method for administering the same
US4652525A (en) 1978-04-19 1987-03-24 The Regents Of The University Of California Recombinant bacterial plasmids containing the coding sequences of insulin genes
US4447538A (en) 1978-04-19 1984-05-08 Regents Of The University Of California Microorganism containing gene for human chorionic somatomammotropin
US4246731A (en) * 1978-06-12 1981-01-27 Miro Carl F Window frame assembly
US4342832A (en) 1979-07-05 1982-08-03 Genentech, Inc. Method of constructing a replicable cloning vehicle having quasi-synthetic genes
AU538665B2 (en) 1979-10-30 1984-08-23 Juridical Foundation, Japanese Foundation For Cancer Research Human interferon dna
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
CA1341567C (en) 1980-01-08 2008-02-19 Charles Weissmann Dna sequences, recombinant dna molecules and processes for producing human interferon - like polypeptides
ES500966A0 (es) 1980-04-03 1982-12-16 Biogen Nv Un metodo de producir un polipeptido que muestra una actividad immunologica obiologica de interferon de fibroblasto hu- mano.
US4414510A (en) 1980-05-28 1983-11-08 General Electric Company Low cost sensing system and method employing anistropic magneto-resistive ferrite member
DE3023787A1 (de) 1980-06-25 1982-01-21 Studiengesellschaft Kohle mbH, 4330 Mülheim Verfahren zur erhoehung der inkorporation und der expression von genetischem material in die kerne von intakten zellen mit hilfe von liposomen
US6610830B1 (en) 1980-07-01 2003-08-26 Hoffman-La Roche Inc. Microbial production of mature human leukocyte interferons
IL63916A0 (en) 1980-09-25 1981-12-31 Genentech Inc Microbial production of human fibroblast interferon
DE3169595D1 (en) 1980-11-10 1985-05-02 Gersonde Klaus Method of preparing lipid vesicles by ultrasonic treatment, the use of this method and apparatus for its application
DE3273787D1 (en) 1981-02-04 1986-11-20 Japan Found Cancer Human interferon-beta gene
NZ199722A (en) 1981-02-25 1985-12-13 Genentech Inc Dna transfer vector for expression of exogenous polypeptide in yeast;transformed yeast strain
JPS57149228A (en) 1981-03-11 1982-09-14 Ajinomoto Co Inc Novel erythropoietin and its preparation
US4792602A (en) 1981-06-19 1988-12-20 Cornell Research Foundation, Inc. Adaptors, and synthesis and cloning of proinsulin genes
CA1204682A (en) 1981-06-19 1986-05-20 Saran A. Narang Adaptors, and synthesis and cloning of proinsulin genes
US4474893A (en) 1981-07-01 1984-10-02 The University of Texas System Cancer Center Recombinant monoclonal antibodies
US4714681A (en) 1981-07-01 1987-12-22 The Board Of Reagents, The University Of Texas System Cancer Center Quadroma cells and trioma cells and methods for the production of same
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4647447A (en) 1981-07-24 1987-03-03 Schering Aktiengesellschaft Diagnostic media
DE3129906C3 (de) 1981-07-24 1996-12-19 Schering Ag Paramagnetische Komplexsalze, deren Herstellung und Mittel zur Verwendung bei der NMR-Diagnostik
IL66614A (en) 1981-08-28 1985-09-29 Genentech Inc Method of constructing a dna sequence encoding a polypeptide,microbial production of human serum albumin,and pharmaceutical compositions comprising it
AU561343B2 (en) 1981-10-19 1987-05-07 Genentech Inc. Human immune interferon by recombinant dna
EP0079739A3 (en) 1981-11-12 1984-08-08 The Upjohn Company Albumin-based nucleotides, their replication and use, and plasmids for use therein
EP0091527A3 (en) 1981-12-14 1984-07-25 The President And Fellows Of Harvard College Dna sequences, recombinant dna molecules and processes for producing human serum albumin-like polypeptides
JPS58118008A (ja) 1982-01-06 1983-07-13 Nec Corp デ−タ処理装置
IT1167610B (it) 1982-01-19 1987-05-13 Cetus Corp Interfreron ibrido multiclasse, composizione farmaceutica che lo contiene e procedimento di produzione
DE3374837D1 (en) 1982-02-17 1988-01-21 Ciba Geigy Ag Lipids in the aqueous phase
US4450103A (en) 1982-03-01 1984-05-22 Cetus Corporation Process for recovering human IFN-β from a transformed microorganism
US4775622A (en) 1982-03-08 1988-10-04 Genentech, Inc. Expression, processing and secretion of heterologous protein by yeast
CA1341562C (en) 1982-03-31 2007-11-27 Tadatsugu Taniguchi Gene coded for interleukin-2 polypeptide, recombinant dna carrying the said gene, a living cell line possessing the recombinant dna, and method for producing interleukin-2 using the said cell
EP0091539B2 (en) 1982-03-31 1996-11-27 Ajinomoto Co., Inc. Gene coding for interleukin-2 polypeptide, recombinant DNA carrying said gene, cell lines possessing the recombinant DNA,and method for producing interleukin-2 using said cells
US4925919A (en) 1984-04-25 1990-05-15 Roland Mertelsmann Purified interleukin 2
US5824330A (en) 1982-04-20 1998-10-20 Sloan-Kettering Institute For Cancer Research Highly purified interleukin-2 and method
US4778879A (en) 1982-04-20 1988-10-18 Sloan-Kettering Institute For Cancer Research Highly purified human interleukin 2 and method
US4499188A (en) 1982-05-05 1985-02-12 Cetus Corporation Bacterial production of heterologous polypeptides under the control of a repressible promoter-operator
US6936694B1 (en) 1982-05-06 2005-08-30 Intermune, Inc. Manufacture and expression of large structural genes
DE3218121A1 (de) 1982-05-14 1983-11-17 Leskovar, Peter, Dr.-Ing., 8000 München Arzneimittel zur tumorbehandlung
EP0102324A3 (de) 1982-07-29 1984-11-07 Ciba-Geigy Ag Lipide und Tenside in wässriger Phase
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
JPS5945835U (ja) 1982-09-16 1984-03-27 株式会社東芝 回路しや断器の消弧装置
US4490289A (en) 1982-09-16 1984-12-25 Hoffmann-La Roche Inc. Homogeneous human interleukin 2
US4992271A (en) 1982-09-23 1991-02-12 Cetus Corporation Formulation for lipophilic IL-2 proteins
US4462940A (en) 1982-09-23 1984-07-31 Cetus Corporation Process for the recovery of human β-interferon-like polypeptides
IE56026B1 (en) 1982-10-19 1991-03-27 Cetus Corp Cysteine-depleted muteins of biologically active proteins
US4741900A (en) 1982-11-16 1988-05-03 Cytogen Corporation Antibody-metal ion complexes
DE3382547D1 (de) 1983-01-12 1992-05-27 Chiron Corp Sekretorische expression in eukaryoten.
US4840934A (en) 1983-01-25 1989-06-20 Eleanor Roosevelt Institute For Cancer Research, Inc. Therapeutic method using T cell growth factor
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US4914026A (en) 1983-04-07 1990-04-03 Chiron Corporation Alpha factor leader sequence directed secretion of insulin
US5015575A (en) 1983-04-07 1991-05-14 Chiron Corporation Hybrid DNA synthesis of insulin
DK172738B1 (da) 1983-04-07 1999-06-21 Chiron Corp Fremgangsmåde til at udtrykke modent insulin og DNA-struktur til anvendelse ved fremgangsmåden
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
JPS60501140A (ja) 1983-04-22 1985-07-25 アムジエン 酵母による外因性ポリペプチドの分泌
NZ207926A (en) 1983-04-25 1988-04-29 Genentech Inc Use of yeast #a#-factor to assist in expression of proteins heterologus to yeast
US5010003A (en) 1983-04-25 1991-04-23 Genentech, Inc. Use of yeast homologous signals to secrete heterologous proteins
CA1196863A (en) 1983-06-08 1985-11-19 Mattheus F.A. Goosen Slow release injectable insulin composition
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
JPS6087792A (ja) 1983-09-23 1985-05-17 ジェネックス・コーポレイション 雑種制御領域
EP0142641B1 (de) 1983-09-26 1991-01-16 Udo Dr. Ehrenfeld Mittel und Erzeugnis für die Diagnose und Therapie von Tumoren sowie zur Behandlung von Schwächen der zelligen und humoralen Immunabwehr
EP0143949B1 (en) 1983-11-01 1988-10-12 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Pharmaceutical composition containing urokinase
JPS60115528A (ja) 1983-11-28 1985-06-22 Takeda Chem Ind Ltd ヒトインタ―ロイキン―２蛋白質を含有する抗腫瘍用または免疫機能低下疾患治療用組成物
GB8334102D0 (en) 1983-12-21 1984-02-01 Searle & Co Interferons with cysteine pattern
NZ210501A (en) 1983-12-13 1991-08-27 Kirin Amgen Inc Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence
US4855238A (en) 1983-12-16 1989-08-08 Genentech, Inc. Recombinant gamma interferons having enhanced stability and methods therefor
GB8334261D0 (en) 1983-12-22 1984-02-01 Bass Plc Fermentation processes
IT1185503B (it) 1984-01-11 1987-11-12 Univ New York Cloni di odna di eritropietina umana
US4908434A (en) 1984-04-25 1990-03-13 Sloan-Kettering Institute For Cancer Research Process for preparing purified interleukin-2
US4908433A (en) 1984-04-25 1990-03-13 Sloan-Kettering Institute For Cancer Research Uses of interleukin-2
CA1213537A (en) 1984-05-01 1986-11-04 Canadian Patents And Development Limited - Societe Canadienne Des Brevets Et D'exploitation Limitee Polypeptide expression method
DK58285D0 (da) 1984-05-30 1985-02-08 Novo Industri As Peptider samt fremstilling og anvendelse deraf
EP0172619A1 (en) 1984-06-20 1986-02-26 Takeda Chemical Industries, Ltd. Novel transformant and use thereof
US4736866B1 (en) 1984-06-22 1988-04-12 Transgenic non-human mammals
JPS61227526A (ja) 1984-07-25 1986-10-09 Chugai Pharmaceut Co Ltd 新規なコロニー刺激因子
US5807715A (en) 1984-08-27 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin
US4687659A (en) 1984-11-13 1987-08-18 Salutar, Inc. Diamide-DTPA-paramagnetic contrast agents for MR imaging
US4959314A (en) 1984-11-09 1990-09-25 Cetus Corporation Cysteine-depleted muteins of biologically active proteins
IL77081A (en) 1984-12-04 1999-10-28 Genetics Inst AND sequence encoding human erythropoietin, a process for its preparation and a pharmacological preparation of human erythropoietin
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4677195A (en) 1985-01-11 1987-06-30 Genetics Institute, Inc. Method for the purification of erythropoietin and erythropoietin compositions
US4970300A (en) 1985-02-01 1990-11-13 New York University Modified factor VIII
GB8504099D0 (en) 1985-02-18 1985-03-20 Wellcome Found Physiologically active substances
DK129385A (da) 1985-03-22 1986-09-23 Novo Industri As Peptider og fremstilling deraf
FR2579224B1 (fr) 1985-03-25 1987-05-22 Genetica Procede de preparation microbiologique de la serum-albumine humaine
ATE63757T1 (de) 1985-03-28 1991-06-15 Chiron Corp Expression durch verwendung von fusionsgenen fuer proteinproduktion.
US4751180A (en) 1985-03-28 1988-06-14 Chiron Corporation Expression using fused genes providing for protein product
JP2532858B2 (ja) 1985-04-01 1996-09-11 セルテツク リミテツド 形質転換したミエロ―マ細胞系
GB8510219D0 (en) 1985-04-22 1985-05-30 Bass Plc Isolation of fermentation products
JPS6229985A (ja) 1985-06-17 1987-02-07 ジエネツクス・コ−ポレ−シヨン クロ−ン化プレプロ−ヒト血清アルブミン遺伝子およびヒト血清アルブミン遺伝子、それらの遺伝子を含むプラスミド、プラスミドにより形質転換された微生物、およびその微生物を用いたプレプロ−ヒト血清アルブミン遺伝子の製造方法
US4980286A (en) 1985-07-05 1990-12-25 Whitehead Institute For Biomedical Research In vivo introduction and expression of foreign genetic material in epithelial cells
US4810643A (en) 1985-08-23 1989-03-07 Kirin- Amgen Inc. Production of pluripotent granulocyte colony-stimulating factor
US5102872A (en) 1985-09-20 1992-04-07 Cetus Corporation Controlled-release formulations of interleukin-2
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
JPH0618778B2 (ja) 1985-10-04 1994-03-16 中外製薬株式会社 白血球減少症治療剤
US5139941A (en) 1985-10-31 1992-08-18 University Of Florida Research Foundation, Inc. AAV transduction vectors
US5576195A (en) 1985-11-01 1996-11-19 Xoma Corporation Vectors with pectate lyase signal sequence
CA1295563C (en) 1985-11-01 1992-02-11 Robert T. Garvin Production of active proteins containing cystine residues
CA1295566C (en) 1987-07-21 1992-02-11 Robert T. Garvin Characterization and structure of genes for protease a and protease b from streptomyces griseus
US5641663A (en) 1985-11-06 1997-06-24 Cangene Corporation Expression system for the secretion of bioactive human granulocyte macrophage colony stimulating factor (GM-CSF) and other heterologous proteins from steptomyces
US5013824A (en) 1985-11-19 1991-05-07 Schering Corporation Human interleukin-4 peptides and conjugates thereof
JPH0780930B2 (ja) 1985-12-26 1995-08-30 三井石油化学工業株式会社 α−オレフインの重合方法
JPH0645551B2 (ja) 1986-01-07 1994-06-15 塩野義製薬株式会社 インタ−ロイキン−２組成物
ES2039209T5 (es) 1986-01-22 1996-07-16 Chugai Pharmaceutical Co Ltd Compuesto farmaceutico que promueve el restablecimiento de la capacidad hemopoyetica.
DE3777845D1 (de) 1986-01-22 1992-05-07 Chugai Pharmaceutical Co Ltd Pharmazeutischer stoff fuer die behandlung von myelogener leukaemie.
DE3772785D1 (de) 1986-01-23 1991-10-17 Squibb & Sons Inc 1-substituiertes-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecan und analoga.
US4885363A (en) 1987-04-24 1989-12-05 E. R. Squibb & Sons, Inc. 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
GB8601597D0 (en) 1986-01-23 1986-02-26 Wilson R H Nucleotide sequences
DE3604868A1 (de) * 1986-02-15 1987-08-20 Behringwerke Ag Insulinderivate, verfahren zu ihrer herstellung und ihre verwendung
FR2594846B1 (fr) 1986-02-21 1989-10-20 Genetica Procede de preparation de la serum albumine humaine mature
EP0237019A3 (en) 1986-03-14 1988-03-09 Toray Industries, Inc. Interferon conjugate and production thereof using recombinant gene
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
IT1203758B (it) 1986-03-27 1989-02-23 Univ Roma Vettori di clonazione e di espressione di geni eterologhi in lieviti e lieviti trasformati con tali vettori
DK179286D0 (da) 1986-04-18 1986-04-18 Nordisk Gentofte Insulinpraeparat
US4765980A (en) 1986-04-28 1988-08-23 International Minerals & Chemical Corp. Stabilized porcine growth hormone
US4859609A (en) 1986-04-30 1989-08-22 Genentech, Inc. Novel receptors for efficient determination of ligands and their antagonists or agonists
US5028422A (en) 1986-05-27 1991-07-02 Schering Corporation Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon
US5985599A (en) 1986-05-29 1999-11-16 The Austin Research Institute FC receptor for immunoglobulin
IT1196484B (it) 1986-07-11 1988-11-16 Sclavo Spa Vettore ad espressione e secrezione in lieviti,utile per la preparazione di proteine eterologhe
GR871067B (en) 1986-07-18 1987-11-19 Chugai Pharmaceutical Co Ltd Process for producing stable pharmaceutical preparation containing granulocyte colony stimulating factor
US4857467A (en) 1986-07-23 1989-08-15 Phillips Petroleum Company Carbon and energy source markers for transformation of strains of the genes Pichia
US4801575A (en) 1986-07-30 1989-01-31 The Regents Of The University Of California Chimeric peptides for neuropeptide delivery through the blood-brain barrier
US5002764A (en) 1986-08-12 1991-03-26 Schering Corporation Treatment of actinic keratoses with alpha2 interferon
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US4929442A (en) 1986-09-26 1990-05-29 Exovir, Inc. Compositions suitable for human topical application including a growth factor and/or related materials
US5508031A (en) 1986-11-21 1996-04-16 Cetus Oncology Corporation Method for treating biological damage using a free-radial scavenger and interleukin-2
JPH01502669A (ja) 1987-03-13 1989-09-14 アムジエン・インコーポレーテツド 精製された血小板由来の成長因子及びその精製方法
US4835260A (en) 1987-03-20 1989-05-30 Genetics Institute, Inc. Erythropoietin composition
GB8707398D0 (en) * 1987-03-27 1987-04-29 Coopers Animal Health Biologically active molecules
HU213344B (en) 1987-04-09 1997-05-28 Delta Biotechnology Ltd Process for producing of stable dezintegrating plasmid-vectors
DE3855504T2 (de) 1987-04-22 1997-01-23 Chiron Corp Rekombinante Herstellung von A-Ketten-Polypeptiden von PDGF
US5258498A (en) 1987-05-21 1993-11-02 Creative Biomolecules, Inc. Polypeptide linkers for production of biosynthetic proteins
US5489425A (en) 1987-06-24 1996-02-06 The Dow Chemical Company Functionalized polyamine chelants
US4994560A (en) 1987-06-24 1991-02-19 The Dow Chemical Company Functionalized polyamine chelants and radioactive rhodium complexes thereof for conjugation to antibodies
DE3855239T2 (de) 1987-07-16 1996-10-31 Nycomed Imaging As Aminocarbonsäure und Derivate
GB8717430D0 (en) 1987-07-23 1987-08-26 Celltech Ltd Recombinant dna product
IL87258A (en) 1987-07-28 1994-02-27 Gist Brocades Nv SECYMOREVYULK surrogate cells and their use for the expression of polypeptides
JPH0622784Y2 (ja) 1987-08-04 1994-06-15 東洋シヤッター株式会社 オ−バ−ドア用可動中柱の高さ調整装置
JP2627899B2 (ja) 1987-08-19 1997-07-09 株式会社 ビタミン研究所 遺伝子封入リポソームの製法
SE459586B (sv) 1987-09-14 1989-07-17 Mta Szegedi Biolog Koezponti Strukturgen som kodar foer autentiskt humant serum albumin och foerfarande foer dess framstaellning
US5336603A (en) 1987-10-02 1994-08-09 Genentech, Inc. CD4 adheson variants
NZ226414A (en) 1987-10-02 1992-07-28 Genentech Inc Cd4 peptide adhesion variants and their preparation and use
JPH0811074B2 (ja) 1987-10-30 1996-02-07 財団法人化学及血清療法研究所 プレアルブミンをコードする遺伝子を組込んだ組換えプラスミドおよびこれを用いたプレアルブミンの製法
GB8726953D0 (en) 1987-11-18 1987-12-23 Delta Biotechnology Ltd Yeast expression system
JP2791418B2 (ja) 1987-12-02 1998-08-27 株式会社ミドリ十字 異種蛋白質の製造方法、組換えｄｎａ、形質転換体
PT89484B (pt) 1988-01-22 1994-03-31 Gen Hospital Corp Genes clonados codificadores de proteinas de fusao ig-cd4 e sua utilizacao
JPH01240191A (ja) 1988-02-16 1989-09-25 Green Cross Corp:The 酵母で機能する新規シグナルペプチドおよびこれを用いた異種蛋白質の分泌発現
JPH01302543A (ja) 1988-02-26 1989-12-06 Fujitsu Ltd トラッキングエラー検知方法とその検知方法に使用する回折格子・光検知器
US5066489A (en) 1988-03-28 1991-11-19 Cetus Corporation Combination therapy of IL-2 and DTIC for the treatment of melanoma
US4999339A (en) 1988-03-28 1991-03-12 Cetus Corporation Combination therapy of IL-2 and DTIC for the treatment of melanoma
US5096885A (en) 1988-04-15 1992-03-17 Genentech, Inc. Human growth hormone formulation
US5763394A (en) * 1988-04-15 1998-06-09 Genentech, Inc. Human growth hormone aqueous formulation
US5981485A (en) 1997-07-14 1999-11-09 Genentech, Inc. Human growth hormone aqueous formulation
US5096707A (en) 1988-04-15 1992-03-17 The United States Of America As Represented By The Department Of Health And Human Services Flavone-8-acetic acid and interleukin-2 in a method of treating certain cancers
US5061488A (en) 1988-04-15 1991-10-29 The United States Of America As Represented Department Of Health & Human Services Flavone-8-acetic acid and interleukin-2 for cancer therapy
GB8809129D0 (en) 1988-04-18 1988-05-18 Celltech Ltd Recombinant dna methods vectors and host cells
IL89989A0 (en) 1988-04-25 1989-12-15 Phillips Petroleum Co Expression of human interleukin-2 in methylotrophic yeasts
IL89992A0 (en) 1988-04-25 1989-12-15 Phillips Petroleum Co Expression of human serum albumin in methylotrophic yeasts
US5126129A (en) 1988-05-23 1992-06-30 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services Cancer therapy using interleukin-2 and flavone compounds
DE58906966D1 (de) 1988-06-23 1994-03-24 Hoechst Ag Mini-Proinsulin, seine Herstellung und Verwendung.
US5756065A (en) 1988-06-24 1998-05-26 The Dow Chemical Company Macrocyclic tetraazacyclododecane conjugates and their use as diagnostic and therapeutic agents
CA1341373C (en) 1988-06-24 2002-07-02 Roberta C. Cheng Macrocyclic bifunctional chelants, complexes thereof and their antibody conjugates
ZA894792B (en) 1988-06-24 1991-04-24 Dow Chemical Co Macrocyclic bifunctional chelants,complexes thereof and their antibody conjugates
US5274119A (en) 1988-07-01 1993-12-28 The Dow Chemical Company Vicinal diols
US4925648A (en) 1988-07-29 1990-05-15 Immunomedics, Inc. Detection and treatment of infectious and inflammatory lesions
FR2635115B1 (fr) 1988-08-05 1992-04-03 Rhone Poulenc Sante Procede de preparation de la serum albumine humaine a partir d'une levure
JPH04501204A (ja) 1988-08-11 1992-03-05 サイオス　ノバ　インコーポレイテッド 異種タンパク発現を安定させる方法およびそれに使用するベクター
US5601819A (en) 1988-08-11 1997-02-11 The General Hospital Corporation Bispecific antibodies for selective immune regulation and for selective immune cell binding
EP1892296A1 (en) 1988-09-02 2008-02-27 Dyax Corporation Generation and selection of recombinant varied binding proteins
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5260202A (en) 1988-09-07 1993-11-09 Delta Biotechnology Limited Fermentation method
JPH02227079A (ja) 1988-10-06 1990-09-10 Tonen Corp ヒト血清アルブミン断片
US5298243A (en) 1988-10-20 1994-03-29 Denki Kagaku Kogyo Kabushiki Kaisha Colony stimulating factor-gelatin conjugate
US5349052A (en) 1988-10-20 1994-09-20 Royal Free Hospital School Of Medicine Process for fractionating polyethylene glycol (PEG)-protein adducts and an adduct for PEG and granulocyte-macrophage colony stimulating factor
JPH02117384A (ja) 1988-10-26 1990-05-01 Tonen Corp 酵母宿主によるヒト血清アルブミンａの製造
US5759802A (en) 1988-10-26 1998-06-02 Tonen Corporation Production of human serum alubumin A
EP0397834B1 (en) 1988-10-28 2000-02-02 Genentech, Inc. Method for identifying active domains and amino acid residues in polypeptides and hormone variants
US5696239A (en) 1988-10-31 1997-12-09 The Dow Chemical Company Conjugates possessing ortho ligating functionality and complexes thereof
US5342604A (en) 1988-10-31 1994-08-30 The Dow Chemical Company Complexes possessing ortho ligating functionality
US5256410A (en) 1988-12-01 1993-10-26 Schering Corporation Treatment of squamous cell carcinoma intralesionally with recombinant human alpha interferon
WO1990006952A1 (en) 1988-12-22 1990-06-28 Kirin-Amgen, Inc. Chemically modified granulocyte colony stimulating factor
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
DK105489D0 (da) 1989-03-03 1989-03-03 Novo Nordisk As Polypeptid
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US5705363A (en) 1989-03-02 1998-01-06 The Women's Research Institute Recombinant production of human interferon τ polypeptides and nucleic acids
JPH04504246A (ja) 1989-03-20 1992-07-30 ザ・ジェネラル・ホスピタル・コーポレーション インシュリン刺激ホルモン
US5693622A (en) 1989-03-21 1997-12-02 Vical Incorporated Expression of exogenous polynucleotide sequences cardiac muscle of a mammal
US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
DK0465529T3 (da) 1989-03-21 1998-10-05 Vical Inc Ekspression af exogene polynukleotidsekvenser i et hvirveldyr
US5231020A (en) 1989-03-30 1993-07-27 Dna Plant Technology Corporation Genetic engineering of novel plant phenotypes
US5328470A (en) 1989-03-31 1994-07-12 The Regents Of The University Of Michigan Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor
DE59000270D1 (de) 1989-04-11 1992-10-01 Boehringer Ingelheim Int Verwendung von mindestens ein cytokin zur herstellung eines arzneimittels zur systemischen behandlung von praeneoplastischen laesionen.
EP0395918A3 (en) 1989-04-13 1991-10-23 Vascular Laboratory, Inc. Plasminogen activator complex of pure pro-urokinase covalently bound by a disulfide bridge to human serum albumin
US5324844A (en) 1989-04-19 1994-06-28 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
US5766883A (en) 1989-04-29 1998-06-16 Delta Biotechnology Limited Polypeptides
GB8909916D0 (en) 1989-04-29 1989-06-14 Delta Biotechnology Ltd Polypeptides
ATE92107T1 (de) 1989-04-29 1993-08-15 Delta Biotechnology Ltd N-terminale fragmente von menschliches serumalbumin enthaltenden fusionsproteinen.
US5332671A (en) 1989-05-12 1994-07-26 Genetech, Inc. Production of vascular endothelial cell growth factor and DNA encoding same
EP0399816B1 (en) 1989-05-24 1995-12-20 Merck & Co. Inc. Purification and characterization of a glioma-derived growth factor
US5808003A (en) 1989-05-26 1998-09-15 Perimmune Holdings, Inc. Polyaminocarboxylate chelators
ATE125869T1 (de) 1989-06-09 1995-08-15 Gropep Pty Ltd Wachstumshormonfusionsproteine.
DK0479909T3 (da) 1989-06-29 1997-04-07 Medarex Inc Bispecifikke reagenser til AIDS-behandling
US5413923A (en) 1989-07-25 1995-05-09 Cell Genesys, Inc. Homologous recombination for universal donor cells and chimeric mammalian hosts
DE3924746A1 (de) 1989-07-26 1991-01-31 Behringwerke Ag Erythropoietin (epo)-peptide und dagegen gerichtete antikoerper
CU22222A1 (es) 1989-08-03 1995-01-31 Cigb Procedimiento para la expresion de proteinas heterologicas producidas de forma fusionada en escherichia coli, su uso, vectores de expresion y cepas recombinantes
FR2650598B1 (fr) * 1989-08-03 1994-06-03 Rhone Poulenc Sante Derives de l'albumine a fonction therapeutique
US5073627A (en) 1989-08-22 1991-12-17 Immunex Corporation Fusion proteins comprising GM-CSF and IL-3
WO1991002754A1 (en) 1989-08-22 1991-03-07 Immunex Corporation Fusion proteins comprising gm-csf and il-3
US5436146A (en) 1989-09-07 1995-07-25 The Trustees Of Princeton University Helper-free stocks of recombinant adeno-associated virus vectors
US6063373A (en) * 1989-09-19 2000-05-16 Maxim Pharmaceuticals, Inc. Enhanced activation of NK cells using an NK cell activator and a hydrogen peroxide scavenger or inhibitor
CA1340994C (en) * 1989-09-21 2000-05-16 Rudolf Edgar Dr. Falk Treatment of conditions and disease
WO1991005052A1 (en) 1989-09-28 1991-04-18 Leningradsky Gosudarstvenny Universitet Method for obtaining a polypeptide with human-interleukin-2 activity, secreted by yeast cells, saccharomyces cerevisiae
FR2653020B1 (fr) 1989-10-17 1993-03-26 Roussel Uclaf Utilisation d'un polypeptide ayant l'activite de l'interleukine 2 humaine pour la preparation de compositions pharmaceutiques destinees au traitement des leucemies.
US5667986A (en) * 1989-10-18 1997-09-16 Delta Biotechnology Limited Yeast promoter for expressing heterologous polypeptides
GB8924021D0 (en) 1989-10-25 1989-12-13 Celltech Ltd Recombinant dna method and vectors for the use therein
WO1991006309A1 (en) 1989-11-03 1991-05-16 Vanderbilt University Method of in vivo delivery of functioning foreign genes
US5676954A (en) 1989-11-03 1997-10-14 Vanderbilt University Method of in vivo delivery of functioning foreign genes
DK608589D0 (da) 1989-12-01 1989-12-01 Holm Arne Kemisk fremgangsmaade
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
JPH03201987A (ja) 1989-12-29 1991-09-03 Tonen Corp ヒト血清アルブミン断片
US5116944A (en) 1989-12-29 1992-05-26 Neorx Corporation Conjugates having improved characteristics for in vivo administration
US5780225A (en) 1990-01-12 1998-07-14 Stratagene Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules
WO1991010737A1 (en) 1990-01-11 1991-07-25 Molecular Affinities Corporation Production of antibodies using gene libraries
EP1690935A3 (en) 1990-01-12 2008-07-30 Abgenix, Inc. Generation of xenogeneic antibodies
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1991011457A1 (en) 1990-01-24 1991-08-08 Buckley Douglas I Glp-1 analogs useful for diabetes treatment
US5545618A (en) 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
JPH04211375A (ja) 1990-02-05 1992-08-03 Ajinomoto Co Inc 合成遺伝子及びそれを用いたヒト血清アルブミンの製造法
US5208018A (en) 1990-03-19 1993-05-04 Brigham And Women's Hospital Treatment of cachexia with interleukin 2
FR2660863B1 (fr) 1990-04-17 1994-01-21 Roussel Uclaf Utilisation d'un polypeptide ayant l'activite de l'interleukine 2 humaine pour preparer une composition pharmaceutique destinee au traitement de cancers primitifs de la plevre.
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
AU7906691A (en) 1990-05-23 1991-12-10 United States of America, as represented by the Secretary, U.S. Department of Commerce, The Adeno-associated virus (aav)-based eucaryotic vectors
GB9013017D0 (en) * 1990-06-11 1990-08-01 Mars Uk Ltd Compounds
WO1992001055A1 (de) 1990-07-10 1992-01-23 Boehringer Ingelheim International Gmbh O-glycosyliertes ifn-alpha
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5225341A (en) 1990-07-19 1993-07-06 The Regents Of The University Of California Biologically safe plant transformation system using a ds transposon
US5202239A (en) 1990-08-07 1993-04-13 Scios Nova Inc. Expression of recombinant polypeptides with improved purification
US5071872A (en) 1990-08-14 1991-12-10 The Ohio State University Research Foundation Method for improving interleukin-2 activity using aci-reductone compounds
DK0546073T3 (da) 1990-08-29 1998-02-02 Genpharm Int Frembringelse og anvendelse af transgene, ikke-humane dyr, der er i stand til at danne heterologe antistoffer
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
IT1242149B (it) 1990-09-27 1994-02-16 Consiglio Nazionale Ricerche Sequenza di nucleotidi codificante per una proteina umana con proprieta' regolative dell'angiogenesi
US5698426A (en) 1990-09-28 1997-12-16 Ixsys, Incorporated Surface expression libraries of heteromeric receptors
ATE175118T1 (de) 1990-10-05 1999-01-15 Medarex Inc Gezielte immunostimulierung mit bispezifischen stoffen
JPH07108232B2 (ja) * 1990-10-09 1995-11-22 エム・ディ・リサーチ株式会社 ペプチド又は蛋白質の製造方法
JPH0638771Y2 (ja) 1990-10-26 1994-10-12 株式会社カンセイ エアバック制御装置
DE69128253T2 (de) 1990-10-29 1998-06-18 Chiron Corp Bispezifische antikörper, verfahren zu ihrer herstellung und deren verwendungen
FR2668368B1 (fr) 1990-10-30 1995-03-10 Roussel Uclaf Utilisation d'un polypeptide ayant l'activite de l'interleukine 2 humaine pour preparer une composition pharmaceutique destinee au traitement des tumeurs malignes epitheliales.
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
US5353535A (en) 1990-11-05 1994-10-11 Plumly George W Floor type advertising apparatus
US5367080A (en) 1990-11-08 1994-11-22 Sterling Winthrop Inc. Complexing agents and targeting radioactive immunoreagents useful in therapeutic and diagnostic imaging compositions and methods
US5830452A (en) 1990-11-20 1998-11-03 Chiron Corporation Method for enhancing the anti-tumor therapeutic index of interleukin-2
ATE164395T1 (de) 1990-12-03 1998-04-15 Genentech Inc Verfahren zur anreicherung von proteinvarianten mit geänderten bindungseigenschaften
US5272070A (en) 1991-03-08 1993-12-21 Board Of Regents, The University Of Texas System Method for the preparation of cell lines producing Man3 GlcNac 2 asparagine-linked gylcans and cell lines produced thereby
EP0503583A1 (en) 1991-03-12 1992-09-16 Takeda Chemical Industries, Ltd. Composition for sustained release of erythropoietin
DE69229454T2 (de) 1991-03-28 2000-01-05 Merck & Co Inc Untereinheit-C des vaskulären endothelialen Zellwachstumsfaktors
CA2108147C (en) 1991-04-10 2009-01-06 Angray Kang Heterodimeric receptor libraries using phagemids
EP0509841A3 (en) 1991-04-18 1993-08-18 Tonen Corporation Co-expression system of protein disulfide isomerase gene and useful polypeptide gene and process for producing the polypeptide using its system
CA2058820C (en) 1991-04-25 2003-07-15 Kotikanyad Sreekrishna Expression cassettes and vectors for the secretion of human serum albumin in pichia pastoris cells
DE69214709T2 (de) 1991-04-26 1997-02-20 Surface Active Ltd Neue Antikörper und Verfahren zu ihrer Verwendung
US5330901A (en) 1991-04-26 1994-07-19 Research Corporation Technologies, Inc. Expression of human serum albumin in Pichia pastoris
FR2676070B1 (fr) 1991-04-30 1994-09-30 Rhone Poulenc Rorer Sa Promoteur de levure et son utilisation.
US5646012A (en) 1991-04-30 1997-07-08 Rhone-Poulenc Rorer S.A. Yeast promoter and use thereof
DE69233482T2 (de) 1991-05-17 2006-01-12 Merck & Co., Inc. Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen
US5304473A (en) 1991-06-11 1994-04-19 Eli Lilly And Company A-C-B proinsulin, method of manufacturing and using same, and intermediates in insulin production
AU2238292A (en) 1991-06-14 1993-01-12 Xoma Corporation Microbially-produced antibody fragments and their conjugates
FR2677996B1 (fr) 1991-06-21 1993-08-27 Rhone Poulenc Rorer Sa Vecteurs de clonage et/ou d'expression preparation et utilisation.
US5851795A (en) 1991-06-27 1998-12-22 Bristol-Myers Squibb Company Soluble CTLA4 molecules and uses thereof
US5844095A (en) 1991-06-27 1998-12-01 Bristol-Myers Squibb Company CTLA4 Ig fusion proteins
AU2147192A (en) 1991-06-28 1993-01-25 Genentech Inc. Method of stimulating immune response using growth hormone
US5633146A (en) * 1991-07-02 1997-05-27 Rhone-Poulenc Rorer S.A. Method for producing recombinant proteins and host cells used therein
US5223408A (en) 1991-07-11 1993-06-29 Genentech, Inc. Method for making variant secreted proteins with altered properties
JPH05292972A (ja) 1991-07-29 1993-11-09 Tonen Corp 改良された酵母発現系
EP0597010A4 (en) 1991-07-31 1996-12-27 Rhone Poulenc Rorer Int Transgenic protein production.
US5723719A (en) 1991-08-08 1998-03-03 Health Research Inc. Transgenic mouse as model for diseases involving dopaminergic dysfunction
DE4126968A1 (de) 1991-08-14 1993-02-18 Detlev Prof Dr Med Ganten Transgene ratten, die in ihrem genom mindestens ein menschliches gen enthalten, das an der blutdruckregulation beteiligt ist
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
NZ245015A (en) * 1991-11-05 1995-12-21 Transkaryotic Therapies Inc Delivery of human growth hormone through the administration of transfected cell lines encoding human growth hormone, which are physically protected from host immune response; the transfected cells and their production
US5641670A (en) 1991-11-05 1997-06-24 Transkaryotic Therapies, Inc. Protein production and protein delivery
US6270989B1 (en) 1991-11-05 2001-08-07 Transkaryotic Therapies, Inc. Protein production and delivery
DE69226197T2 (de) 1991-11-08 1999-02-11 Somatogen Inc Hämoglobine als arzneimittelabgabesystem
WO1993011236A1 (en) 1991-12-02 1993-06-10 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US6348327B1 (en) * 1991-12-06 2002-02-19 Genentech, Inc. Non-endocrine animal host cells capable of expressing variant proinsulin and processing the same to form active, mature insulin and methods of culturing such cells
US5428139A (en) 1991-12-10 1995-06-27 The Dow Chemical Company Bicyclopolyazamacrocyclophosphonic acid complexes for use as radiopharmaceuticals
ES2204899T3 (es) 1992-01-07 2004-05-01 Elan Pharmaceuticals, Inc. Modelos de animales transgenicos para la enfermedad de alzheimer.
GB9200417D0 (en) 1992-01-09 1992-02-26 Bagshawe Kenneth D Cytotoxic drug therapy
FR2686620B1 (fr) 1992-01-27 1995-06-23 Rhone Poulenc Rorer Sa Serum-albumine humaine, preparation et utilisation.
FR2686899B1 (fr) * 1992-01-31 1995-09-01 Rhone Poulenc Rorer Sa Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant.
FR2686900B1 (fr) * 1992-01-31 1995-07-21 Rhone Poulenc Rorer Sa Nouveaux polypeptides ayant une activite de stimulation des colonies de granulocytes, leur preparation et compositions pharmaceutiques les contenant.
FR2686901A1 (fr) 1992-01-31 1993-08-06 Rhone Poulenc Rorer Sa Nouveaux polypeptides antithrombotiques, leur preparation et compositions pharmaceutiques les contenant.
CA2131528C (en) 1992-03-05 2004-07-13 Philip E. Thorpe Methods and compositions for targeting the vasculature of solid tumors
US5230886A (en) 1992-03-18 1993-07-27 Trustees Of Boston University Tumor cell suppression
USRE37302E1 (en) 1992-03-19 2001-07-31 Novo Nordisk A/S Peptide
DK36392D0 (da) 1992-03-19 1992-03-19 Novo Nordisk As Anvendelse af kemisk forbindelse
DK36492D0 (da) 1992-03-19 1992-03-19 Novo Nordisk As Praeparat
US5733743A (en) 1992-03-24 1998-03-31 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
US5460954A (en) 1992-04-01 1995-10-24 Cheil Foods & Chemicals, Inc. Production of human proinsulin using a novel vector system
US5229109A (en) 1992-04-14 1993-07-20 Board Of Regents, The University Of Texas System Low toxicity interleukin-2 analogues for use in immunotherapy
AU658072B2 (en) 1992-06-09 1995-03-30 Hoppe Ag Latch and lockset system
PL176007B1 (pl) 1992-06-15 1999-03-31 Scios Inc Nowe pochodne polipeptydu GLP-1
US5686268A (en) * 1992-06-19 1997-11-11 Pfizer Inc. Fused proteins
US5505931A (en) 1993-03-04 1996-04-09 The Dow Chemical Company Acid cleavable compounds, their preparation and use as bifunctional acid-labile crosslinking agents
FR2694294B1 (fr) 1992-07-30 1994-09-09 Rhone Poulenc Rorer Sa Promoteur de levure et son utilisateur.
AU686567C (en) 1992-07-31 2002-08-08 Genentech Inc. Human growth hormone aqueous formulation
US5602307A (en) 1992-08-12 1997-02-11 Baylor College Of Medicine Non-human animal having predefined allele of a cellular adhesion gene
DE4226971C2 (de) 1992-08-14 1997-01-16 Widmar Prof Dr Tanner Modifizierte Pilzzellen und Verfahren zur Herstellung rekombinanter Produkte
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
US5728553A (en) * 1992-09-23 1998-03-17 Delta Biotechnology Limited High purity albumin and method of producing
US5731490A (en) 1992-09-29 1998-03-24 The Ontario Cancer Institute Mutant mouse lacking the expression of interferon regulatory factor 1 (IRF-1)
AU5171293A (en) 1992-10-14 1994-05-09 Regents Of The University Of Colorado, The Ion-pairing of drugs for improved efficacy and delivery
FR2697752B1 (fr) * 1992-11-10 1995-04-14 Rhone Poulenc Rorer Sa Compositions antitumorales contenant des dérivés du taxane.
TW402639B (en) 1992-12-03 2000-08-21 Transkaryotic Therapies Inc Protein production and protein delivery
US5478745A (en) 1992-12-04 1995-12-26 University Of Pittsburgh Recombinant viral vector system
US5441050A (en) 1992-12-18 1995-08-15 Neoprobe Corporation Radiation responsive surgical instrument
US6221958B1 (en) * 1993-01-06 2001-04-24 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
US5489743A (en) 1993-01-19 1996-02-06 Amgen Inc. Transgenic animal models for thrombocytopenia
US5593972A (en) 1993-01-26 1997-01-14 The Wistar Institute Genetic immunization
US5441734A (en) 1993-02-25 1995-08-15 Schering Corporation Metal-interferon-alpha crystals
US5780021A (en) 1993-03-05 1998-07-14 Georgetown University Method for treating type 1 diabetes using α-interferon and/or β-i
NZ250844A (en) 1993-04-07 1996-03-26 Pfizer Treatment of non-insulin dependant diabetes with peptides; composition
US6284727B1 (en) 1993-04-07 2001-09-04 Scios, Inc. Prolonged delivery of peptides
AU6709794A (en) 1993-04-21 1994-11-08 Brigham And Women's Hospital Erythropoietin muteins with enhanced activity
GB9308581D0 (en) 1993-04-26 1993-06-09 Univ Manitoba A method for induction of antigen-specific suppression of immune-response
WO1994029469A2 (en) 1993-06-07 1994-12-22 Vical Incorporated Plasmids suitable for gene therapy
DK82893D0 (da) * 1993-07-08 1993-07-08 Novo Nordisk As Peptid
US5512459A (en) 1993-07-20 1996-04-30 Bionebraska, Inc. Enzymatic method for modification or recombinant polypeptides
CZ285508B6 (cs) 1993-08-09 1999-08-11 Edward Baral Použití trifenylethylenových antiestrogenů pro zvyšování citlivosti rakovinných buněk k lyzi zprostředkované zabíječskými buňkami
ZA946122B (en) 1993-08-17 1995-03-20 Amgen Inc Erythropoietin analogs
WO1995005848A1 (en) 1993-08-24 1995-03-02 Novo Nordisk A/S Protracted glp-1
GB9317618D0 (en) 1993-08-24 1993-10-06 Royal Free Hosp School Med Polymer modifications
US5521086A (en) 1993-09-16 1996-05-28 Cephalon, Inc. Secretion sequence for the production of a heterologous protein in yeast
US5643575A (en) 1993-10-27 1997-07-01 Enzon, Inc. Non-antigenic branched polymer conjugates
US5459031A (en) 1993-11-05 1995-10-17 Amgen Inc. Methods for controlling sialic acid derivatives in recombinant glycoproteins
EP0733070A1 (en) 1993-12-08 1996-09-25 Genzyme Corporation Process for generating specific antibodies
EP0658568A1 (en) 1993-12-09 1995-06-21 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5705483A (en) 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
WO1995016708A1 (en) 1993-12-17 1995-06-22 Novo Nordisk A/S Proinsulin-like compounds
DK144093D0 (ja) 1993-12-23 1993-12-23 Novo Nordisk As
DK0744958T3 (da) 1994-01-31 2003-10-20 Univ Boston Polyklonale antistofbiblioteker
GB9404270D0 (en) 1994-03-05 1994-04-20 Delta Biotechnology Ltd Yeast strains and modified albumins
US6608182B1 (en) 1994-03-08 2003-08-19 Human Genome Sciences, Inc. Human vascular endothelial growth factor 2
US5652352A (en) 1994-03-31 1997-07-29 Amgen Inc. Afamin: a human serum albumin-like gene
US5629286A (en) 1994-03-31 1997-05-13 Brewitt; Barbara Homeopathic dilutions of growth factors
US5646113A (en) 1994-04-07 1997-07-08 Genentech, Inc. Treatment of partial growth hormone insensitivity syndrome
FR2719593B1 (fr) 1994-05-06 1996-05-31 Rhone Poulenc Rorer Sa Nouveaux polypeptides biologiquement actifs, leur préparation et composition pharmaceutique les contenant.
GB9409496D0 (en) 1994-05-12 1994-06-29 London Health Ass Method for improving glycaemic control in diabetes
GB9411356D0 (en) 1994-06-07 1994-07-27 Delta Biotechnology Ltd Yeast strains
US5516637A (en) 1994-06-10 1996-05-14 Dade International Inc. Method involving display of protein binding pairs on the surface of bacterial pili and bacteriophage
US5985660A (en) 1994-06-15 1999-11-16 Systemix, Inc. Method of identifying biological response modifiers involved in dendritic and/or lymphoid progenitor cell proliferation and/or differentiation
US5639642A (en) 1994-06-16 1997-06-17 Novo Nordisk A/S Synthetic leader peptide sequences
US5623054A (en) 1994-06-23 1997-04-22 The General Hospital Corporation Crucifer AFT proteins and uses thereof
NZ290089A (en) 1994-07-27 1999-05-28 Queensland Inst Med Res Recombinant polyepitope cytotoxic t lymphocyte (ctl) vaccines
JPH0853500A (ja) 1994-08-11 1996-02-27 Asahi Glass Co Ltd 融合タンパク質および該タンパク質をコードする遺伝子
JPH0851982A (ja) 1994-08-11 1996-02-27 Asahi Glass Co Ltd ヒト血清アルブミンをコードする改変された遺伝子
JPH0859509A (ja) 1994-08-16 1996-03-05 Teijin Ltd サイトメガロウイルス抗原血症治療剤およびサイトメガロウイルス感染症治療剤
US5574008A (en) 1994-08-30 1996-11-12 Eli Lilly And Company Biologically active fragments of glucagon-like insulinotropic peptide
US6071923A (en) 1994-09-16 2000-06-06 Bar-Ilan University Retinoyloxy aryl-substituted alkylene butyrates useful for the treatment of cancer and other proliferative diseases
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
EP0792278B1 (en) 1994-11-07 2007-06-13 Human Genome Sciences, Inc. Tumor necrosis factor-gamma
FR2726471B1 (fr) 1994-11-07 1997-01-31 Pf Medicament Procede pour ameliorer l'immunogenicite d'un compose immunogene ou d'un haptene et application a la preparation de vaccins
FR2726576B1 (fr) 1994-11-07 1997-01-31 Pf Medicament Production de peptides analogues de peptides hydrophobes, peptide recombinant, sequence d'adn correspondante
AT403167B (de) 1994-11-14 1997-11-25 Immuno Ag Selektion und expression von fremdproteinen mittels eines selektions-amplifikations-systems
AU4415796A (en) 1994-12-07 1996-06-26 Bionebraska, Inc. Production of c-terminal amidated peptides from recombinant protein constructs
EP0796335A1 (en) 1994-12-07 1997-09-24 Bionebraska, Inc. Production of peptides using recombinant fusion protein constructs
JPH11501506A (ja) * 1994-12-12 1999-02-09 ベス イスラエル デアコネス メディカル センター キメラ型サイトカインおよびその利用
US20010006943A1 (en) 1994-12-23 2001-07-05 Ejvind Jensen Protracted GLP-1 compositions
DE69529998D1 (de) 1994-12-23 2003-04-24 Novo Nordisk As Glp-1 zusammensetzungen mit verlängerter wirkdauer
US5652224A (en) 1995-02-24 1997-07-29 The Trustees Of The University Of Pennsylvania Methods and compositions for gene therapy for the treatment of defects in lipoprotein metabolism
US5928939A (en) 1995-03-01 1999-07-27 Ludwig Institute For Cancer Research Vascular endothelial growth factor-b and dna coding therefor
TW426523B (en) 1995-04-06 2001-03-21 Hoffmann La Roche Interferon solution
US6184201B1 (en) 1995-04-14 2001-02-06 Nps Allelix Corp. Intestinotrophic glucagon-like peptide-2 analogs
WO1996034095A1 (en) 1995-04-27 1996-10-31 Human Genome Sciences, Inc. Human tumor necrosis factor receptors
DE69637481T2 (de) 1995-04-27 2009-04-09 Amgen Fremont Inc. Aus immunisierten Xenomäusen stammende menschliche Antikörper gegen IL-8
AU2466895A (en) 1995-04-28 1996-11-18 Abgenix, Inc. Human antibodies derived from immunized xenomice
EP0741188A3 (en) 1995-05-05 1999-07-14 Eli Lilly And Company Single chain insulin with high bioactivity
US5728915A (en) 1995-05-08 1998-03-17 Children's Hospital, Inc. Transgenic mice which express simian SV 40 T-antigen under control of the retinoblastoma gene promoter
US6387365B1 (en) 1995-05-19 2002-05-14 Schering Corporation Combination therapy for chronic hepatitis C infection
US5741815A (en) 1995-06-02 1998-04-21 Lai; Ching-San Methods for in vivo reduction of nitric oxide levels and compositions useful therefor
US5804162A (en) 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
US5728707A (en) * 1995-07-21 1998-03-17 Constantia Gruppe Treatment and prevention of primary and metastatic neoplasms with salts of aminoimidazole carboxamide
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
JPH0940699A (ja) * 1995-07-28 1997-02-10 Sanwa Kagaku Kenkyusho Co Ltd ポリペプチド及びその用途
US5840542A (en) 1995-07-28 1998-11-24 Mogam Biotechnology Research Institute Method for manufacture of proinsulin with high export yield
DE19530865A1 (de) 1995-08-22 1997-02-27 Michael Dr Med Nauck Wirkstoff sowie Mittel zur parenteralen Ernährung
JPH0995455A (ja) 1995-09-29 1997-04-08 Sumitomo Pharmaceut Co Ltd 腎機能改善剤
US5766620A (en) 1995-10-23 1998-06-16 Theratech, Inc. Buccal delivery of glucagon-like insulinotropic peptides
US5849322A (en) 1995-10-23 1998-12-15 Theratech, Inc. Compositions and methods for buccal delivery of pharmaceutical agents
US5702717A (en) 1995-10-25 1997-12-30 Macromed, Inc. Thermosensitive biodegradable polymers based on poly(ether-ester)block copolymers
CA2329474C (en) 1995-11-02 2002-02-26 Schering Corporation Continuous low-dose cytokine infusion therapy
US6048964A (en) 1995-12-12 2000-04-11 Stryker Corporation Compositions and therapeutic methods using morphogenic proteins and stimulatory factors
JP3533857B2 (ja) * 1995-12-25 2004-05-31 富士レビオ株式会社 梅毒トレポネマ融合抗原及び該融合抗原を用いた抗梅毒トレポネマ抗体の測定方法
GB9526733D0 (en) * 1995-12-30 1996-02-28 Delta Biotechnology Ltd Fusion proteins
AU718254B2 (en) 1996-01-19 2000-04-13 Betagene, Inc. Recombinant expression of proteins from secretory cell lines
US6087129A (en) 1996-01-19 2000-07-11 Betagene, Inc. Recombinant expression of proteins from secretory cell lines
US6110707A (en) 1996-01-19 2000-08-29 Board Of Regents, The University Of Texas System Recombinant expression of proteins from secretory cell lines
US5767097A (en) 1996-01-23 1998-06-16 Icn Pharmaceuticals, Inc. Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes
US6150337A (en) 1996-01-23 2000-11-21 Icn Pharmaceuticals, Inc. Specific modulation of Th1/Th2 cytokine expression by Ribavirin in activated T-lymphocytes
JP2978435B2 (ja) 1996-01-24 1999-11-15 チッソ株式会社 アクリロキシプロピルシランの製造方法
US5616724A (en) 1996-02-21 1997-04-01 Cephalon, Inc. Fused pyrrolo[2,3-c]carbazole-6-ones
DE19639601A1 (de) 1996-02-28 1997-09-04 Bayer Ag Parapockenviren, die Fremd-DNA enthalten, ihre Herstellung und ihre Verwendung in Impfstoffen
US6045788A (en) * 1996-02-28 2000-04-04 Cornell Research Foundation, Inc. Method of stimulation of immune response with low doses of IL-2
DE69738695D1 (de) 1996-03-01 2008-06-26 Novo Nordisk As Peptid zur Appetitzügelung, dessen Zusammensetzungen und Verwendung
US5912229A (en) 1996-03-01 1999-06-15 Novo Nordisk Als Use of a pharmaceutical composition comprising an appetite-suppressing peptide
JP3794748B2 (ja) * 1996-03-04 2006-07-12 第一アスビオファーマ株式会社 メタノール代謝系を有する微生物の培養法
WO1997033904A1 (en) 1996-03-12 1997-09-18 Human Genome Sciences, Inc. Death domain containing receptors
JP4318751B2 (ja) 1996-03-13 2009-08-26 ノボザイムス、 バイオファーマ、 ユーケー、 リミテッド 発酵制御
CA2248136A1 (en) 1996-03-21 1997-09-25 Human Genome Sciences, Inc. Human endometrial specific steroid-binding factor i, ii and iii
WO1997039132A1 (en) 1996-04-16 1997-10-23 University Of Miami Stabilized preparations of human troponins and modifications thereof, diagnostic assay methods and assay kits
US5919815A (en) 1996-05-22 1999-07-06 Neuromedica, Inc. Taxane compounds and compositions
ATE196844T1 (de) 1996-05-22 2000-10-15 Protarga Inc Zusammensetzungen die konjugate von cis- docosahexaenoic-säure und taxotere enthalten
US6300065B1 (en) * 1996-05-31 2001-10-09 Board Of Trustees Of The University Of Illinois Yeast cell surface display of proteins and uses thereof
ES2150832B1 (es) 1996-06-12 2001-06-16 Fichtel & Sachs Ag Dispositivo de maniobra para la maniobra, en particular maniobra neumatica, de un embrague de friccion.
US6110891A (en) 1996-06-21 2000-08-29 Alizyme Therapeutics Ltd. Lectin compositions and uses thereof
GB2318352A (en) 1996-06-25 1998-04-22 Dejan Markovic Polypeptides mimicking the activity of human erythropoietin
GB9613858D0 (en) 1996-07-02 1996-09-04 Cortecs Ltd Hydrophobic preparations
US5932547A (en) 1996-07-03 1999-08-03 Alza Corporation Non-aqueous polar aprotic peptide formulations
US6110703A (en) 1996-07-05 2000-08-29 Novo Nordisk A/S Method for the production of polypeptides
US6828426B1 (en) 1996-07-15 2004-12-07 Chugai Seiyaku Kabushiki Kaisha VEGF-like factor
PE99498A1 (es) 1996-07-26 1999-01-21 Novartis Ag Polipeptidos de fusion
US5959075A (en) * 1996-08-02 1999-09-28 Zymogenetics, Inc. Testis-specific insulin homolog polypeptides
ES2316153T3 (es) 1996-08-16 2009-04-01 Human Genome Sciences, Inc. Endoquina alfa humana.
DE69738749D1 (de) 1996-08-16 2008-07-17 Schering Corp Zelloberflächen-antigen aus säugetieren und verwandte reagenzien
DK0956339T3 (da) 1996-08-23 2006-01-30 Licentia Oy Rekombinant vaskulær endotelcellevækstfaktor D (VEGF-D)
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
US6277819B1 (en) 1996-08-30 2001-08-21 Eli Lilly And Company Use of GLP-1 or analogs in treatment of myocardial infarction
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
US5922761A (en) 1996-09-06 1999-07-13 Medinox, Inc. Methods for in vivo reduction of iron levels and compositions useful therefor
WO1998011136A1 (en) 1996-09-09 1998-03-19 Novo Nordisk A/S A cDNA AND PEPTIDE WITH RELATION TO CANCER AND WEIGHT LOSS
US20020052309A1 (en) 1996-09-11 2002-05-02 Athanasius A. Anagnostou Method of treating endothelial injury
AU7364696A (en) 1996-09-18 1998-04-14 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like genes
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
US5955508A (en) * 1996-10-15 1999-09-21 Loyola University Of Chicago Method for the enhancement of lymphocyte activity against opportunistic microbial pathogens
AU4988697A (en) 1996-10-24 1998-05-15 Vion Pharmaceuticals, Inc. Monophosphate prodrugs of beta-l-fd4c and beta-l-fddc as potent antiviral agents
PT939804E (pt) 1996-10-25 2005-11-30 Human Genome Sciences Inc Neutroquina alfa
US5908830A (en) 1996-10-31 1999-06-01 Merck & Co., Inc. Combination therapy for the treatment of diabetes and obesity
EP1306092A3 (en) 1996-11-05 2003-05-07 Eli Lilly & Company Use of GLP-1 and analogs administered peripherally, in regulation of obesity
UA65549C2 (uk) * 1996-11-05 2004-04-15 Елі Ліллі Енд Компані Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція
AU4863797A (en) 1996-11-12 1998-06-03 Novo Nordisk A/S Use of glp-1 peptides
ATE387495T1 (de) 1996-12-03 2008-03-15 Amgen Fremont Inc Vollkommen humane antikörper die egfr binden
US6130248A (en) 1996-12-30 2000-10-10 Bar-Ilan University Tricarboxylic acid-containing oxyalkyl esters and uses thereof
CN1247567A (zh) 1997-01-14 2000-03-15 人体基因组科学有限公司 肿瘤坏死因子受体6α和6β
AU6238698A (en) 1997-01-14 1998-08-03 Human Genome Sciences, Inc. Tumor necrosis factor receptor 5
JP2001527387A (ja) * 1997-01-24 2001-12-25 ノボ ノルディスク アクティーゼルスカブ 合成リーダーペプチド配列
PT1012274E (pt) 1997-01-28 2007-08-14 Craig A Rosen Receptor 4 contendo um domínio de morte (dm4; receptor de morte 4), membro da super-família do ftn e ligação a liart (ap02)
WO1998032466A1 (en) 1997-01-29 1998-07-30 Polymasc Pharmaceuticals Plc Pegylation process
CA2280894A1 (en) 1997-02-13 1998-08-20 Applied Phytologics, Inc. Production of mature proteins in plants
US7026447B2 (en) * 1997-10-09 2006-04-11 Human Genome Sciences, Inc. 53 human secreted proteins
US6110955A (en) 1997-03-11 2000-08-29 Beacon Laboratories, Inc. Metabolically stabilized oxyalkylene esters and uses thereof
US6110970A (en) 1997-03-11 2000-08-29 Beacon Laboratories, Inc. Nitrogen-containing oxyalkylene esters and uses thereof
US5939455A (en) 1997-03-11 1999-08-17 Beacon Laboratories, Inc. Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives
US6124495A (en) 1997-03-11 2000-09-26 Beacon Laboratories, Inc. Unsaturated oxyalkylene esters and uses thereof
US6030961A (en) * 1997-03-11 2000-02-29 Bar-Ilan Research & Development Co., Ltd. Oxyalkylene phosphate compounds and uses thereof
US5846774A (en) 1997-03-21 1998-12-08 Bionebraska, Inc. Chlorella virus promoters
US6627729B1 (en) * 1997-03-24 2003-09-30 Zymogenetics, Inc. TML peptides
US5981488A (en) 1997-03-31 1999-11-09 Eli Lillly And Company Glucagon-like peptide-1 analogs
TR199902553T2 (xx) 1997-04-14 2000-03-21 Micromet Gesellschaft F�R Biomedizinische Forschung Mbh �nsan v�cuduna kar�� antijen resept�rlerinin �retimi i�in yeni metod ve kullan�mlar�.
TW577759B (en) 1997-04-18 2004-03-01 Ipsen Pharma Biotech Sustained release compositions in the form of microcapsules or implants and the process for their preparation
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
JP2002511070A (ja) 1997-05-30 2002-04-09 ヒューマン ジノーム サイエンシーズ，インコーポレイテッド ヒト腫瘍壊死因子受容体ｔｒ１０
AU7830398A (en) 1997-06-11 1998-12-30 Human Genome Sciences, Inc. Human tumor necrosis factor receptor tr9
GB9713412D0 (en) 1997-06-26 1997-08-27 Delta Biotechnology Ltd Improved protein expression strains
ES2208798T3 (es) 1997-09-01 2004-06-16 Aventis Pharma Deutschland Gmbh Eritropoyetina humana recombinante con un perfil de glicosilacion ventajoso.
JP3201987B2 (ja) 1997-09-09 2001-08-27 株式会社オーレック 草刈装置
HUP9701554D0 (en) 1997-09-18 1997-11-28 Human Oltoanyagtermeloe Gyogys Pharmaceutical composition containing plazma proteins
US6172046B1 (en) * 1997-09-21 2001-01-09 Schering Corporation Combination therapy for eradicating detectable HCV-RNA in patients having chronic Hepatitis C infection
US6472373B1 (en) 1997-09-21 2002-10-29 Schering Corporation Combination therapy for eradicating detectable HCV-RNA in antiviral treatment naive patients having chronic hepatitis C infection
EP1136075B1 (en) 1997-09-21 2003-01-15 Schering Corporation Combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
EP1224940B2 (de) 1997-09-23 2010-08-11 Rentschler Biotechnologie GmbH Flüssige Interferon-Beta Formulierungen
US6004573A (en) 1997-10-03 1999-12-21 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
US6201072B1 (en) * 1997-10-03 2001-03-13 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
US6117949A (en) 1998-10-01 2000-09-12 Macromed, Inc. Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
CA2305690A1 (en) 1997-10-09 1999-04-22 Human Genome Sciences, Inc. 53 human secreted proteins
WO1999028346A1 (de) 1997-12-03 1999-06-10 Roche Diagnostics Gmbh Erythropoietin mit hoher spezifischer aktivität
JP2001525371A (ja) 1997-12-05 2001-12-11 イーライ・リリー・アンド・カンパニー Ｇｌｐ−１製剤
DE69822505T2 (de) * 1997-12-08 2005-01-20 Bristol-Myers Squibb Co. Neue metformin-salze und verfahren
ES2590912T3 (es) 1997-12-08 2016-11-24 Merck Patent Gmbh Proteínas de fusión heterodiméricas útiles para inmunoterapia dirigida y estimulación general del sistema inmunitario
US6380357B2 (en) 1997-12-16 2002-04-30 Eli Lilly And Company Glucagon-like peptide-1 crystals
KR100253916B1 (ko) 1997-12-29 2000-05-01 김충환 사람 인슐린 전구체의 제조방법
US5951996A (en) 1998-02-04 1999-09-14 Czeizler Zaharia; Veronica L. Treatment of chronic diffuse GI bleeding with erythropoietin
US6221378B1 (en) * 1998-02-10 2001-04-24 Generex Pharmaceuticals Incorporated Mixed micellar delivery system and method of preparation
US6017545A (en) * 1998-02-10 2000-01-25 Modi; Pankaj Mixed micellar delivery system and method of preparation
AU759058C (en) 1998-02-13 2005-09-15 Amylin Pharmaceuticals, Inc. Inotropic and diuretic effects of exendin and GLP-1
DE69942306D1 (de) 1998-02-27 2010-06-10 Novo Nordisk As Abkömmlinge von glp-1 analogen
AU2610599A (en) * 1998-02-27 1999-09-15 Novo Nordisk A/S N-terminally truncated glp-1 derivatives
EP1061947B1 (en) 1998-03-13 2004-06-16 Novo Nordisk A/S Stabilized aqueous glucagon solutions comprising detergents
AU3087599A (en) 1998-03-19 1999-10-11 Bionebraska, Inc. Human appetite control by glucagon-like peptide receptor binding compounds
AU3047299A (en) 1998-04-13 1999-11-01 Modex Therapeutiques, S.A. Methods of delivering glp-1
CA2270320A1 (en) 1998-04-28 1999-10-28 Patricia Lee Brubaker Novel microsphere composition
CN1119352C (zh) 1998-05-15 2003-08-27 中国科学院上海生物化学研究所 人血清白蛋白在毕赤酵母中的表达与纯化
MY129244A (en) 1998-05-15 2007-03-30 Schering Corp Combination therapy comprising ribavirin and interferon alpha in antiviral treatment naive patients having chronic hepatitis c infection.
SE9802080D0 (sv) 1998-06-11 1998-06-11 Hellstroem Pharmaceutical composition for the treatment of functional dyspepsia and/or irritable bowel syndrome and new use of substances therein
WO1999064061A1 (en) 1998-06-12 1999-12-16 Bionebraska, Inc. GLUCAGON-LIKE PEPTIDE-1 IMPROVES β-CELL RESPONSE TO GLUCOSE IN SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE
EP1088084B1 (en) * 1998-06-15 2006-09-13 GTC Biotherapeutics, Inc. Erythropoietin analog-human serum albumin fusion protein
CN1105727C (zh) 1998-06-17 2003-04-16 上海海济医药生物工程有限公司 重组人血清白蛋白的生产方法
EP1091979B1 (en) 1998-06-30 2006-09-20 Novo Nordisk A/S Seeding crystals for the preparation of peptides or proteins
AU8508398A (en) 1998-07-15 2000-02-07 Wisconsin Alumni Research Foundation Treatment of diabetes with synthetic beta cells
EP1100530B1 (en) 1998-07-31 2003-10-08 Novo Nordisk A/S In-vitro stimulation of beta cell proliferation
GB9817084D0 (en) 1998-08-06 1998-10-07 Wood Christopher B A method for promoting extra-heptic production of proteins for the correction of hypoalbuminaemia,anaemia,thrombocytopenia and/or coagulation disorders
AU776514B2 (en) 1998-08-10 2004-09-09 General Hospital Corporation, The Differentiation of non-insulin producing cells into insulin producing cells by GLP-1 or exendin-4 and uses thereof
US6346543B1 (en) * 1998-08-17 2002-02-12 Aventis Pharma S.A. Use of a taxoid to treat abnormal cell proliferation in the brain
EA200100289A1 (ru) 1998-08-28 2001-10-22 Эли Лилли Энд Компани Способ введения инсулинотропных пептидов
MY155270A (en) 1998-09-24 2015-09-30 Lilly Co Eli Use of glp-1 or analogs in treatment of stroke
US6290987B1 (en) 1998-09-27 2001-09-18 Generex Pharmaceuticals, Inc. Mixed liposome pharmaceutical formulation with amphiphiles and phospholipids
US6193997B1 (en) * 1998-09-27 2001-02-27 Generex Pharmaceuticals Inc. Proteinic drug delivery system using membrane mimetics
US6429197B1 (en) 1998-10-08 2002-08-06 Bionebraska, Inc. Metabolic intervention with GLP-1 or its biologically active analogues to improve the function of the ischemic and reperfused brain
US6284725B1 (en) 1998-10-08 2001-09-04 Bionebraska, Inc. Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue
US7259136B2 (en) * 1999-04-30 2007-08-21 Amylin Pharmaceuticals, Inc. Compositions and methods for treating peripheral vascular disease
AU6425699A (en) 1998-10-16 2000-05-08 Cornell Research Foundation Inc. Methods of inhibiting platelet activation and recruitment
SI1813624T1 (sl) 1998-10-23 2010-12-31 Amgen Inc Postopki in sestavki za prepeäśevanje in zdravljenje anemije
JP2002531067A (ja) 1998-10-30 2002-09-24 ノボザイムス アクティーゼルスカブ 低下したアレルゲン性を有するグリコシル化タンパク質
EP1135493A2 (en) 1998-11-30 2001-09-26 Eli Lilly And Company Erythropoietic compounds
US6048891A (en) 1998-12-17 2000-04-11 Loma Linda University Medical Center Use of γ-tocopherol and its oxidative metabolite LLU-α in the treatment of natriuretic disease
US6312665B1 (en) 1998-12-21 2001-11-06 Generex Pharmaceuticals Incorporated Aerosol formulations for buccal and pulmonary application
US6294153B1 (en) 1998-12-21 2001-09-25 Generex Pharmaceuticals, Inc. Aerosol pharmaceutical formulation for pulmonary and nasal delivery
US6271200B1 (en) 1998-12-21 2001-08-07 Generex Pharmaceuticals Inc. Proteinic drug delivery system using aerosolized membrane-mimetic amphiphiles
ATE307603T1 (de) 1998-12-22 2005-11-15 Lilly Co Eli Lagerstabile flüssige zusammensetzungen von glucagon-ähnlichem peptid-1
GB9902000D0 (en) 1999-01-30 1999-03-17 Delta Biotechnology Ltd Process
ATE244558T1 (de) 1999-04-16 2003-07-15 Novo Nordisk As Trockene formbare arzneistoffformulierung
US6287588B1 (en) 1999-04-29 2001-09-11 Macromed, Inc. Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof
US6348192B1 (en) * 1999-05-11 2002-02-19 Bayer Corporation Interleukin-2 mutein expressed from mammalian cells
DE19921537A1 (de) 1999-05-11 2000-11-23 Dieter Hoersch Verfahren zur Induzierung von Zellwachstum durch Verwendung geeigneter Mittel
US6514500B1 (en) 1999-10-15 2003-02-04 Conjuchem, Inc. Long lasting synthetic glucagon like peptide {GLP-!}
MXPA01011845A (es) 1999-05-19 2002-06-21 Lexigen Pharm Corp Expresion y exportacion de proteinas de interferon-alfa como proteinas de fusion fc.
US6344180B1 (en) 1999-06-15 2002-02-05 Bionebraska, Inc. GLP-1 as a diagnostic test to determine β-cell function and the presence of the condition of IGT and type II diabetes
EP1849475A1 (en) 1999-06-21 2007-10-31 Eli Lilly & Company Synergistic use of thiazolidinediones with glucagon-like peptide-1 and agonists thereof to treat non-insulin dependent diabetes
PE20010288A1 (es) 1999-07-02 2001-03-07 Hoffmann La Roche Derivados de eritropoyetina
JP2003505043A (ja) 1999-07-19 2003-02-12 ジーピーシー バイオテック インコーポレイテッド 血清アルブミンのキメラポリペプチド及びそれらに関する利用
US20020048571A1 (en) 1999-07-19 2002-04-25 Jeno Gyuris Chimeric polypeptides of serum albumin and uses related thereto
US7144574B2 (en) * 1999-08-27 2006-12-05 Maxygen Aps Interferon β variants and conjugates
TW200528436A (en) 1999-09-22 2005-09-01 Bristol Myers Squibb Co Substituted acid derivatives useful as antiodiabetic and antiobesity agents and method
PH12000002657B1 (en) 1999-10-12 2006-02-21 Bristol Myers Squibb Co C-aryl glucoside SGLT2 inhibitors
WO2001029242A2 (en) 1999-10-21 2001-04-26 Monsanto Company Post-translational modification of recombinant proteins produced in plants
AU1226901A (en) 1999-10-22 2001-05-08 Amgen, Inc. Biodegradable microparticles with novel erythropoietin stimulating protein
DE60037535D1 (de) 1999-11-03 2008-01-31 Novo Nordisk As Verwendung eines wachstumshormons oder eines wachstumshormon-sekretion fördernden mittels zur appetit-unterdrückung bzw. sättigungsinduktion
CA2324801A1 (en) 1999-11-10 2001-05-10 Andrew Gordon Swick Use of apo b secretion/mtp inhibitors and anti-obesity agents
US6569832B1 (en) * 1999-11-12 2003-05-27 Novo Nordisk A/S Inhibition of beta cell degeneration
CA2391080A1 (en) 1999-11-12 2001-05-25 Merck Patent Gesellschaft Mit Beschraenkter Haftung Erythropoietin forms with improved properties
IL149933A0 (en) 1999-12-06 2002-11-10 Gen Hospital Corp Pancreatic stem cells and their use in transplantation
US20020025306A1 (en) 2000-01-07 2002-02-28 Baetge Edward E. Methods of increasing the glucose responsiveness of pancreatic ss-cells
EP1125579A3 (en) 2000-01-18 2003-01-02 Pfizer Products Inc. Uses of agrp-melanocortin receptor binding modulating compounds
KR20020073184A (ko) 2000-01-27 2002-09-19 일라이 릴리 앤드 캄파니 글루카곤 유사 펩티드 1 화합물을 용해시키는 방법
AU2001228327A1 (en) 2000-01-31 2001-08-14 Novo-Nordisk A/S Crystallisation of a glp-1 analogue
CA2402733A1 (en) 2000-03-14 2001-09-20 Burkhard Goke Effects of glucagon-like peptide-1 (7-36) on antro-pyloro-duodenal motility
JP4237375B2 (ja) * 2000-03-31 2009-03-11 アスビオファーマ株式会社 虚血性疾患の処置又は予防に用いる医薬組成物
AU2001244677A1 (en) * 2000-04-07 2001-10-23 Eiken Kagaku Kabushiki Kaisha Method of amplifying nucleic acid by using double-stranded nucleic acid as template
US6946134B1 (en) * 2000-04-12 2005-09-20 Human Genome Sciences, Inc. Albumin fusion proteins
US20050100991A1 (en) 2001-04-12 2005-05-12 Human Genome Sciences, Inc. Albumin fusion proteins
PT1274728E (pt) 2000-04-21 2008-06-20 Amgen Inc Métodos e composições para a prevenção e tratamento de anemia
IL142707A0 (en) 2000-04-27 2002-03-10 Pfizer Prod Inc Methods of treating obesity using a neurotensin receptor ligand
JP3967594B2 (ja) * 2000-05-15 2007-08-29 エフ．ホフマン−ラ ロシュ アーゲー 新しい薬剤組成物
WO2001087322A2 (en) 2000-05-17 2001-11-22 Bionebraska, Inc. Peptide pharmaceutical formulations
KR100518046B1 (ko) * 2000-05-19 2005-10-04 아밀린 파마슈티칼스, 인크. Ｇｌｐ-1을 사용한 급성 관상동맥 증후군의 치료
HU229208B1 (en) 2000-06-16 2013-09-30 Lilly Co Eli Glucagon-like peptide-1 analogs
EP1326630B1 (en) 2000-09-18 2008-05-28 Sanos Bioscience A/S Use of glp-2 peptides
ATE470448T1 (de) 2000-10-20 2010-06-15 Amylin Pharmaceuticals Inc Behandlung von hypoaktivem myokard und diabetischer herzmyopathie mit einem glp-1 peptid
US7101561B2 (en) * 2000-12-01 2006-09-05 Innogenetics N.V. Purified hepatitis C virus envelope proteins for diagnostic and therapeutic use
AU2002221222A1 (en) 2000-12-04 2002-06-18 Biovitrum Ab Novel method and use
JP2004528014A (ja) 2000-12-07 2004-09-16 イーライ・リリー・アンド・カンパニー Ｇｌｐ−１融合タンパク質
CN1501809B (zh) 2000-12-13 2012-10-10 伊莱利利公司 应用胰高血糖素样促胰岛肽的长期治疗方案
WO2002048192A2 (en) 2000-12-13 2002-06-20 Eli Lilly And Company Amidated glucagon-like peptide-1
WO2002066062A2 (en) 2001-02-01 2002-08-29 Drucker Daniel J Enhancement of glp-2 activity
KR100399337B1 (ko) 2001-02-07 2003-09-26 드림바이오젠 주식회사 단백질의 무세포 번역후수식법
AU2002235731A1 (en) 2001-03-07 2002-09-19 Novo Nordisk A/S Combined use of derivatives of glp-1 analogs and ppar ligands
US20020169128A1 (en) 2001-04-09 2002-11-14 Geroge Sigounas Erythropoietin ameliorates chemotherapy-induced toxicity in vivo
US20050054051A1 (en) * 2001-04-12 2005-03-10 Human Genome Sciences, Inc. Albumin fusion proteins
US7507413B2 (en) 2001-04-12 2009-03-24 Human Genome Sciences, Inc. Albumin fusion proteins
US20050244931A1 (en) * 2001-04-12 2005-11-03 Human Genome Sciences, Inc. Albumin fusion proteins
US20060084794A1 (en) 2001-04-12 2006-04-20 Human Genome Sciences, Inc. Albumin fusion proteins
WO2002085406A1 (en) 2001-04-24 2002-10-31 Restoragen, Inc. Methods and compositions for treating conditions associated with insulin resistance
WO2002097038A2 (en) * 2001-05-25 2002-12-05 Human Genome Sciences, Inc. Chemokine beta-1 fusion proteins
US7144863B2 (en) 2001-06-01 2006-12-05 Eli Lilly And Company GLP-1 formulations with protracted time action
DK1397124T3 (da) 2001-06-20 2007-04-02 Merck Sante Sas Anvendelse af diabetesmidler til fremstilling af et lægemiddel med helende virkning
US20030119734A1 (en) 2001-06-28 2003-06-26 Flink James M. Stable formulation of modified GLP-1
EP1411968B1 (en) 2001-07-31 2008-09-17 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Glp-1 exendin-4 peptide analogs and uses thereof
US20040002468A1 (en) 2001-08-08 2004-01-01 Genzyme Corporation Methods of treating diabetes and other blood sugar disorders
EP1423136A4 (en) 2001-08-10 2007-07-25 Epix Pharm Inc POLYPEPTIDE CONJUGATES HAVING INCREASED CIRCULATION HALF-VIES
BR0212080A (pt) 2001-08-23 2006-04-04 Lilly Co Eli composto de glp-1, método de estimulação de receptor de glp-1 em um indivìduo necessitando de tal estimulação, e, uso de um composto de glp-1
WO2003030821A2 (en) * 2001-10-05 2003-04-17 Human Genome Sciences, Inc. Albumin fusion proteins
ES2516041T3 (es) * 2001-10-10 2014-10-30 Ratiopharm Gmbh Remodelación y glicoconjugación de la hormona del crecimiento humano (hGH)
CA2471363C (en) 2001-12-21 2014-02-11 Human Genome Sciences, Inc. Albumin fusion proteins
WO2003054182A2 (en) 2001-12-21 2003-07-03 Nexia Biotechnologies, Inc. Production of butyrylcholinesterases in transgenic mammals
US20080167238A1 (en) * 2001-12-21 2008-07-10 Human Genome Sciences, Inc. Albumin Fusion Proteins
CA2484556A1 (en) 2001-12-21 2003-07-24 Human Genome Sciences, Inc. Albumin fusion proteins
KR101271635B1 (ko) 2001-12-21 2013-06-12 휴먼 게놈 사이언시즈, 인코포레이티드 알부민 융합 단백질
US20080194481A1 (en) 2001-12-21 2008-08-14 Human Genome Sciences, Inc. Albumin Fusion Proteins
WO2005003296A2 (en) 2003-01-22 2005-01-13 Human Genome Sciences, Inc. Albumin fusion proteins
US6682190B2 (en) * 2002-01-31 2004-01-27 Hewlett-Packard Development Company, L.P. Controlling media curl in print-zone
EP1572936A2 (en) 2002-03-05 2005-09-14 Eli Lilly And Company Heterologous g-csf fusion proteins
JP2005535569A (ja) 2002-04-04 2005-11-24 ノボ・ノルデイスク・エー／エス Ｇｌｐ−１アゴニスト及び心臓血管合併症
CN1241946C (zh) * 2002-07-01 2006-02-15 美国福源集团 对多种细胞具刺激增生作用的人血清白蛋白重组融合蛋白
JP4211375B2 (ja) 2002-12-10 2009-01-21 セイコーエプソン株式会社 データ転送制御方法、データ転送回路装置およびこれを備えた印刷装置
US6913890B2 (en) 2002-12-18 2005-07-05 Palo Alto Research Center Incorporated Process for preparing albumin protein conjugated oligonucleotide probes
AU2004251145C1 (en) 2003-06-12 2011-04-14 Eli Lilly And Company GLP-1 analog fusion proteins
NZ548612A (en) * 2004-02-09 2009-11-27 Human Genome Sciences Inc Albumin fusion proteins comprising tandem GLP-1
US20060051859A1 (en) * 2004-09-09 2006-03-09 Yan Fu Long acting human interferon analogs
WO2006073890A2 (en) 2004-12-24 2006-07-13 Amylin Pharmaceuticals, Inc. Use of glp-1 and agonists thereof to prevent cardiac myocyte apoptosis
US8946149B2 (en) 2005-04-11 2015-02-03 Amylin Pharmaceuticals, Llc Use of exendin and analogs thereof to delay or prevent cardiac remodeling
MX2008001865A (es) 2005-08-12 2008-04-15 Human Genome Sciences Inc Proteinas de fusion de albumina.
US8008257B2 (en) * 2005-10-20 2011-08-30 University Of Ottawa Heart Institute ANF fusion proteins
AU2007267833B2 (en) * 2006-05-26 2012-07-26 Amylin Pharmaceuticals, Llc Composition and methods for treatment of congestive heart failure
WO2007146038A2 (en) 2006-06-07 2007-12-21 Human Genome Sciences, Inc. Albumin fusion proteins
US20090209469A1 (en) 2006-08-04 2009-08-20 Dennis Kim Use of Exendins and GLP-1 Receptor Agonists for Altering Lipoprotein Particle Size and Subclass Composition

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
EP0058481A1 (en) 1981-02-16 1982-08-25 Zeneca Limited Continuous release pharmaceutical compositions
EP0133988A2 (de) 1983-08-02 1985-03-13 Hoechst Aktiengesellschaft Regulatorische Peptide enthaltende pharmazeutische Präparate mit protrahierter Freisetzung und Verfahren zu deren Herstellung
JPH0336516B2 (ja) 1985-10-21 1991-05-31 Kogyo Gijutsuin
EP0251744A2 (en) 1986-06-27 1988-01-07 Delta Biotechnology Limited Process for the genetic modification of yeast
EP0258067A2 (en) 1986-08-29 1988-03-02 Delta Biotechnology Limited Yeast promoter
EP0322094A1 (en) 1987-10-30 1989-06-28 Delta Biotechnology Limited N-terminal fragments of human serum albumin
EP0330451A2 (en) 1988-02-22 1989-08-30 Toa Nenryo Kogyo Kabushiki Kaisha A cDNA coding for human normal serum albumin a, and a process for production of the albumin
WO1990001063A1 (en) 1988-07-23 1990-02-08 Delta Biotechnology Limited New secretory leader sequences
EP0387319A1 (en) 1988-07-23 1990-09-19 Delta Biotechnology Ltd SECRETORIC LEADER SEQUENCES.
EP0361991A2 (en) 1988-08-05 1990-04-04 Rhone-Poulenc Sante Method for the microbiological preparation of human serum albumin and other heterologous proteins from a yeast
WO1997033899A1 (en) 1996-03-14 1997-09-18 Human Genome Sciences, Inc. Apoptosis inducing molecule i
WO1997034911A1 (en) 1996-03-22 1997-09-25 Human Genome Sciences, Inc. Apoptosis inducing molecule ii
WO1998030213A2 (en) 1997-01-08 1998-07-16 Paracelsian, Inc. Use of the ah receptor and ah receptor ligands to treat or prevent the cytopathicity of viral infection
WO1998050347A1 (en) 1997-05-05 1998-11-12 The Regents Of The University Of California Naphthols useful in antiviral methods
WO1998054366A1 (en) 1997-06-02 1998-12-03 Subsidiary No. 3, Inc. Compositions and methods for inhibiting human immunodeficiency virus infection by down-regulating human cellular genes
WO1999023105A1 (en) 1997-11-03 1999-05-14 Human Genome Sciences, Inc. Vegi, an inhibitor of angiogenesis and tumor growth
WO1999049830A2 (de) 1998-03-27 1999-10-07 Retro-Tech Gmbh Anti-virale wirkung von propolis durch inhibition viraler nukleinsäure polymerasen
WO1999056764A1 (en) 1998-04-30 1999-11-11 Teijin Limited Method for preventing or treating a human immunodeficiency virus infection
WO1999066936A1 (en) 1998-06-24 1999-12-29 Emory University Use of 3'-azido-2',3'-dideoxyuridine in combination with further anti-hiv drugs for the manufacture of a medicament for the treatment of hiv
WO2000069911A1 (en) 1999-05-17 2000-11-23 Conjuchem, Inc. Long lasting insulinotropic peptides
WO2001079258A1 (en) 2000-04-12 2001-10-25 Human Genome Sciences, Inc. Albumin fusion proteins

Non-Patent Citations (39)

* Cited by examiner, † Cited by third party
Title
B. C. JOHNSON,: "POST-TRANSLATIONAL COVALENT MODIFICATION OF PROTEINS", 1983, ACADEMIC PRESS, pages: 1 - 12
BECKER; GUARENTE, METHODS ENZYMOL, vol. 194, 1990, pages 182
BERENT ET AL., BIOTECH., vol. 3, 1985, pages 208
BOWIE ET AL.: "Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions", SCIENCE, vol. 247, 1990, pages 1306 - 1310
BRUTLAG ET AL., COMP. APP. BIOSCI., vol. 6, 1990, pages 237 - 245
CHEN ET AL., NAT. MED., vol. 3, 1997, pages 1110 - 16
CLELAND ET AL., CRIT. REV. THERAPEUTIC DRUG CARRIER SYSTEMS, vol. 10, 1993, pages 307 - 377
CREIGHTON: "Proteins: Structures and Molecular Principles", 1983, W.H. FREEMAN & CO.
CUNNINGHAM; WELLS, SCIENCE, vol. 244, 1989, pages 1081 - 1085
D.R. HIGGINS AND J. CREGG,: "Pichia Protocols: Methods in Molecular Biology", 1998, THE HUMANA PRESS
DELGADO ET AL., CRIT REV. THERA. DRUG CARRIER SYS., vol. 9, 1992, pages 249 - 304
DOBELI ET AL., J. BIOTECHNOLOGY, vol. 7, 1988, pages 199 - 216
ELLIS, S.B. ET AL., MOL. CELL. BIOL., vol. 5, 1985, pages 1111 - 21
GANDERTON; JONES: "Drug Delivery to the Respiratory Tract", 1987, ELLIS HORWOOD
GAYLE, J. BIOL. CHEM., vol. 268, 1993, pages 22105 - 22111
GONDA, CRITICAL REVIEWS IN THERAPEUTIC DRUG CARRIER SYSTEMS, vol. 6, 1990, pages 273 - 313
HOFFMAN; WINSTON, GENETICS, vol. 124, 1990, pages 807 - 816
HUNKAPILLER ET AL., NATURE, vol. 310, 1984, pages 105 - 111
KOUTZ, P.J ET AL., YEAST, vol. 5, 1989, pages 167 - 77
LANGER ET AL., J. BIOMED. MATER. RES., vol. 15, 1981, pages 167 - 277
LANGER, CHEM. TECH., vol. 12, 1982, pages 98 - 105
LEWIN, B: "Genes n", 1985, JOHN WILEY & SONS
MAUNDRELL, J. BIOL. CHEM., vol. 265, 1990, pages 10857 - 10864
PINCKARD ET AL., CLIN. EXP. IMMUNOL., vol. 2, 1967, pages 331 - 340
POZNANSKY ET AL., FEBS LETT., vol. 239, 1988, pages 18
RAEBURN ET AL., PHARMACOL. TOXICOL. METHODS, vol. 27, 1992, pages 143 - 159
RATTAN ET AL., ANN. N.Y. ACAD. SCI., vol. 663, 1992, pages 48 - 62
ROBBINS ET AL., DIABETES, vol. 36, 1987, pages 838 - 845
RON ET AL., J. BIOL. CHEM., vol. 268, 1993, pages 2984 - 2988
SAIKI ET AL., SCIENCE, vol. 239, 1988, pages 487 - 491
SCOTT HEGENHART, FOOD PRODUCT DESIGN, December 1993 (1993-12-01)
See also references of EP1463751A4
SEIFTER ET AL., METH. ENZYMOL., vol. 182, 1990, pages 626 - 646
SIDMAN ET AL., BIOPOLYMERS, vol. 22, 1983, pages 547 - 556
SOUTHERN, J. MOT. BIOL., vol. 98, 1975, pages 503
T. E. CREIGHTON: "PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed.", 1993, W. H. FREEMAN AND COMPANY
TAKAHASHI ET AL., INT. IMMUNOL., vol. 6, 1994, pages 1567 - 1574
TSCHOPP, J.F. ET AL., NUCL. ACIDS RES., vol. 15, 1987, pages 3859 - 76
YANG ET AL., PNAS, vol. 94, 1997, pages 11567 - 72

Cited By (140)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8642542B2 (en) 1995-12-30 2014-02-04 Novozymes Biopharma Dk A/S Recombinant fusion proteins to growth hormone and serum albumin
US7393823B1 (en) 1999-01-20 2008-07-01 Oregon Health And Science University HER-2 binding antagonists
US9545086B2 (en) 1999-01-25 2017-01-17 Biogen Ma Inc. BAFF, inhibitors thereof and their use in the modulation of B-cell response and treatment of autoimmune disorders
US10080785B2 (en) 2000-04-12 2018-09-25 Novozymes Biopharma Dk A/S Albumin fusion proteins
US9775888B2 (en) 2000-04-12 2017-10-03 Albumedix A/S Treatment with factor ix-albumin fusion protein
US8946156B2 (en) 2000-04-12 2015-02-03 Human Genome Sciences, Inc. Albumin Fusion Proteins
US7785599B2 (en) 2000-04-12 2010-08-31 Human Genome Sciences, Inc. Albumin fusion proteins
US8022270B2 (en) 2000-07-31 2011-09-20 Biolex Therapeutics, Inc. Expression of biologically active polypeptides in duckweed
US7632983B2 (en) 2000-07-31 2009-12-15 Biolex Therapeutics, Inc. Expression of monoclonal antibodies in duckweed
US7271149B2 (en) 2000-12-07 2007-09-18 Eli Lilly And Company GLP-1 fusion proteins
US8981061B2 (en) 2001-03-20 2015-03-17 Novo Nordisk A/S Receptor TREM (triggering receptor expressed on myeloid cells) and uses thereof
US8231878B2 (en) 2001-03-20 2012-07-31 Cosmo Research & Development S.P.A. Receptor trem (triggering receptor expressed on myeloid cells) and uses thereof
US8993517B2 (en) 2001-12-21 2015-03-31 Human Genome Sciences, Inc. Albumin fusion proteins
US7977306B2 (en) 2001-12-21 2011-07-12 Human Genome Sciences, Inc. Albumin fusion proteins
US8287859B2 (en) 2001-12-21 2012-10-16 Human Genome Sciences, Inc. Methods of reducing toxicity and effects of cocaine by administering a butyrylcholinesterase (BChE)-albumin fusion protein
US8071539B2 (en) 2001-12-21 2011-12-06 Human Genome Sciences, Inc. Albumin fusion proteins
US7238660B2 (en) 2001-12-21 2007-07-03 Human Genome Sciences, Inc. Albumin fusion proteins
US8252739B2 (en) 2001-12-21 2012-08-28 Human Genome Sciences, Inc. Albumin fusion proteins
US9296809B2 (en) 2001-12-21 2016-03-29 Human Genome Sciences, Inc. Albumin fusion proteins
US8513189B2 (en) 2001-12-21 2013-08-20 Human Genome Sciences, Inc. Albumin fusion proteins
US9221896B2 (en) 2001-12-21 2015-12-29 Human Genome Sciences, Inc. Albumin fusion proteins
US7799759B2 (en) 2001-12-21 2010-09-21 Human Genome Sciences, Inc. Albumin fusion proteins
US7189690B2 (en) 2001-12-21 2007-03-13 Human Genome Sciences, Inc. Albumin fusion proteins
US8084200B2 (en) 2002-11-15 2011-12-27 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
WO2005026392A2 (en) * 2003-09-11 2005-03-24 Liat Mintz Compositions, reagents and kits for and methods of diagnosing, monitoring and treating obesity and/or diabetes
WO2005026392A3 (en) * 2003-09-11 2005-08-11 Liat Mintz Compositions, reagents and kits for and methods of diagnosing, monitoring and treating obesity and/or diabetes
JP2007504825A (ja) * 2003-09-11 2007-03-08 リアット・ミンツ 肥満および／または糖尿病を診断、モニタリング、および治療するための組成物、試薬、およびキット、ならびにその方法
JP2007508332A (ja) * 2003-10-17 2007-04-05 ノボ　ノルディスク　アクティーゼルスカブ 併用療法
WO2005054286A3 (en) * 2003-12-03 2006-11-30 Delta Biotechnology Ltd Interleukin-11 fusion proteins
EP1729795B1 (en) * 2004-02-09 2016-02-03 Human Genome Sciences, Inc. Albumin fusion proteins
JP2007522806A (ja) * 2004-02-09 2007-08-16 ヒューマン　ジノーム　サイエンシーズ，　インコーポレイテッド アルブミン融合蛋白質
CN102816241A (zh) * 2004-02-09 2012-12-12 人类基因科学公司 清蛋白融合蛋白
JP2012140448A (ja) * 2004-02-09 2012-07-26 Human Genome Sciences Inc アルブミン融合蛋白質
AU2005211776B2 (en) * 2004-02-11 2012-02-02 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs and polypeptides comprising the same
US20070219131A1 (en) * 2004-04-15 2007-09-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
US8604185B2 (en) 2004-07-20 2013-12-10 Genentech, Inc. Inhibitors of angiopoietin-like 4 protein, combinations, and their use
US7740846B2 (en) 2004-07-20 2010-06-22 Genentech, Inc. Inhibitors of angiopoietin-like 4 protein, combinations, and their use
US8633155B2 (en) 2004-07-20 2014-01-21 Genentech, Inc. Methods of using angiopoietin-like 4 protein to stimulate proliferation of pre-adipocytes
US7371384B2 (en) 2004-07-20 2008-05-13 Genentech, Inc. Compositions and methods of using angiopoietin-like 4 protein antibody
EP2332563A2 (en) 2004-10-13 2011-06-15 The Washington University Use of BAFF to treat sepsis
US7572451B2 (en) 2004-10-25 2009-08-11 Cytos Biotechnology Ag Gastric inhibitory polypeptide (GIP) antigen arrays and uses thereof
US7959924B2 (en) 2004-10-25 2011-06-14 Cytos Biotechnology Ag Gastric inhibitory polypeptide (GIP) antigen arrays and uses thereof
US9273111B2 (en) 2004-11-29 2016-03-01 Universite De Lorraine Therapeutic TREM-1 peptides
US10603357B2 (en) 2004-11-29 2020-03-31 Bristol-Myers Squibb Company Therapeutic TREM-1 peptides
EP2769990A2 (en) 2004-12-02 2014-08-27 Domantis Limited Bispecific domain antibodies targeting serum albumin and GLP-1 or PYY
EP1924596A2 (en) * 2005-08-12 2008-05-28 Human Genome Sciences, Inc. Albumin fusion proteins
EP1924596A4 (en) * 2005-08-12 2009-07-29 Human Genome Sciences Inc ALBUM INFUSION PROTEINS
WO2007056681A2 (en) 2005-11-04 2007-05-18 Smithkline Beecham Corporation Methods for administering hypoglycemic agents
EP3095456A1 (en) 2005-11-04 2016-11-23 Glaxosmithkline LLC Methods for administering hypoglycemic agents
WO2007064437A3 (en) * 2005-11-10 2008-12-11 Receptor Biologix Inc Methods for production of receptor and ligand isoforms
WO2007064437A2 (en) * 2005-11-10 2007-06-07 Receptor Biologix, Inc. Methods for production of receptor and ligand isoforms
US20080260746A1 (en) * 2005-11-24 2008-10-23 Laboratoires Serono Sa Erythropoietin Polypeptides and Uses Thereof
US8765915B2 (en) 2006-02-06 2014-07-01 Csl Behring Gmbh Modified coagulation factor VIIa with extended half-life
US8759295B2 (en) 2006-03-21 2014-06-24 Amylin Pharmaceuticals, Llc Peptide-peptidase inhibitor conjugates and methods of using same
AU2007227202B2 (en) * 2006-03-21 2013-08-22 Amylin Pharmaceuticals, Llc Peptide-peptidase inhibitor conjugates and methods of using same
WO2007112940A3 (en) * 2006-03-31 2008-01-03 Ablynx Nv Albumin-derived amino acid sequence, use thereof for increasing the half-life of therapeutic proteins and of other therapeutic compounds and entities, and constructs comprising the same
WO2007112940A2 (en) * 2006-03-31 2007-10-11 Ablynx N.V. Albumin-derived amino acid sequence, use thereof for increasing the half-life of therapeutic proteins and of other therapeutic compounds and entities, and constructs comprising the same
US8334365B2 (en) 2006-06-07 2012-12-18 Human Genome Sciences, Inc. Albumin fusion proteins
US8969538B2 (en) 2006-06-07 2015-03-03 Human Genome Sciences, Inc. Albumin fusion proteins
EP2054437A2 (en) * 2006-08-07 2009-05-06 Teva Biopharmaceuticals USA, Inc. Albumin-insulin fusion proteins
US9505823B2 (en) 2006-08-07 2016-11-29 TEV A Biopharmaceuticals USA, Inc. Albumin-insulin fusion proteins
EP2423222B1 (en) 2007-01-30 2015-04-29 Epivax, Inc. Regulatory t cell epitopes, compositions and uses thereof
EP2423222B2 (en) † 2007-01-30 2020-07-29 Epivax, Inc. Regulatory t cell epitopes, compositions and uses thereof
US20130261025A1 (en) * 2007-02-22 2013-10-03 Lauri Diehl Methods for detecting inflammatory bowel disease
US8598314B2 (en) 2007-09-27 2013-12-03 Amylin Pharmaceuticals, Llc Peptide-peptidase-inhibitor conjugates and methods of making and using same
AU2008319332B2 (en) * 2007-10-31 2014-05-08 Human Genome Sciences, Inc. Albumin fusion proteins
WO2009058322A1 (en) 2007-10-31 2009-05-07 Human Genome Sciences, Inc. Albumin fusion proteins
WO2009121804A1 (en) 2008-03-31 2009-10-08 Glaxo Group Limited Drug fusions and conjugates
EP2860260A1 (en) * 2008-04-11 2015-04-15 Merrimack Pharmaceuticals, Inc. Human serum albumin linkers and conjugates thereof
WO2010020777A3 (en) * 2008-08-19 2010-06-10 The Secretary Of State For Defence Dstl Protein expression
WO2010020777A2 (en) * 2008-08-19 2010-02-25 The Secretary Of State For Defence Dstl Protein expression
US9566246B2 (en) 2008-09-17 2017-02-14 Chiasma Inc. Pharmaceutical compositions and related methods of delivery
US11400159B2 (en) 2008-09-17 2022-08-02 Amryt Endo, Inc. Pharmaceutical compositions and related methods of delivery
US11969471B2 (en) 2008-09-17 2024-04-30 Amryt Endo, Inc. Pharmaceutical compositions and related methods of delivery
US9265812B2 (en) 2008-09-17 2016-02-23 Chiasma, Inc. Pharmaceutical compositions and related methods of delivery
US11986529B2 (en) 2008-09-17 2024-05-21 Amryt Endo, Inc. Pharmaceutical compositions and related methods of delivery
US8993519B2 (en) 2009-01-16 2015-03-31 Teva Pharmaceutical Industries Ltd. Method of treatment for neutropenia using stable formulations of recombinant human albumin-human granulocyte colony stimulating factor
US11555061B2 (en) 2009-02-11 2023-01-17 Albumedix, Ltd Albumin variants and conjugates
WO2010108937A2 (en) 2009-03-27 2010-09-30 Glaxo Group Limited Drug fusions and conjugates
WO2011039096A1 (en) 2009-09-30 2011-04-07 Glaxo Group Limited Drug fusions and conjugates with extended half life
US10696732B2 (en) 2009-10-30 2020-06-30 Albumedix, Ltd Albumin variants
US8541373B2 (en) 2009-12-08 2013-09-24 Teva Pharmaceutical Industries Ltd. BChE albumin fusions for the treatment of cocaine abuse
CN102939304A (zh) * 2010-04-09 2013-02-20 诺维信生物制药丹麦公司 白蛋白衍生物和变体
CN106977608A (zh) * 2010-04-09 2017-07-25 阿尔布麦狄克斯公司 白蛋白衍生物和变体
US10233228B2 (en) 2010-04-09 2019-03-19 Albumedix Ltd Albumin derivatives and variants
WO2011124718A1 (en) * 2010-04-09 2011-10-13 Novozymes A/S Albumin derivatives and variants
CN102939304B (zh) * 2010-04-09 2017-04-19 阿尔布麦狄克斯公司 白蛋白衍生物和变体
WO2012059486A1 (en) 2010-11-01 2012-05-10 Novozymes Biopharma Dk A/S Albumin variants
US10155803B2 (en) 2011-03-03 2018-12-18 Zymeworks Inc. Multivalent heteromultimer scaffold design and constructs
US10711051B2 (en) 2011-03-03 2020-07-14 Zymeworks Inc. Multivalent heteromultimer scaffold design and constructs
WO2012136790A1 (en) 2011-04-07 2012-10-11 Glaxo Group Limited Compositions comprising fusion proteins or conjugates with an improved half -life
WO2012136792A2 (en) 2011-04-07 2012-10-11 Glaxo Group Limited Cck compositions
WO2012150319A1 (en) 2011-05-05 2012-11-08 Novozymes Biopharma Dk A/S Albumin variants
WO2013006675A1 (en) 2011-07-05 2013-01-10 Novozymes Biopharma Uk Limited Albumin formulation and use
US10844349B2 (en) 2011-07-05 2020-11-24 Albumedix Ltd. Albumin formulation and use
US10711050B2 (en) 2011-11-18 2020-07-14 Albumedix Ltd Variant serum albumin with improved half-life and other properties
US10906965B2 (en) 2012-02-15 2021-02-02 Novo Nordisk A/S Methods of treating autoimmune disease or chronic inflammation wtih antibodies that bind peptidoglycan recognition protein 1
US9663568B2 (en) 2012-02-15 2017-05-30 Novo Nordisk A/S Antibodies that bind peptidoglycan recognition protein 1
US9550830B2 (en) 2012-02-15 2017-01-24 Novo Nordisk A/S Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1)
US9000127B2 (en) 2012-02-15 2015-04-07 Novo Nordisk A/S Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1)
US10150809B2 (en) 2012-02-15 2018-12-11 Bristol-Myers Squibb Company Antibodies that bind peptidoglycan recognition protein 1
US10906975B2 (en) 2012-02-15 2021-02-02 Novo Nordisk A/S Methods of treating autoimmune disease or chronic inflammation with antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1)
US10189904B2 (en) 2012-02-15 2019-01-29 Novo Nordisk A/S Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1)
US9944691B2 (en) 2012-03-16 2018-04-17 Albumedix A/S Albumin variants
US10329340B2 (en) 2012-03-16 2019-06-25 Albumedix Ltd Albumin variants
WO2013135896A1 (en) 2012-03-16 2013-09-19 Novozymes Biopharma Dk A/S Albumin variants
EP3330283A2 (en) 2012-03-16 2018-06-06 Albumedix A/S Albumin variants
WO2013171570A1 (en) 2012-05-16 2013-11-21 Glaxo Group Limited Polypeptide loaded poca nanoparticles for oral administration
CN104768571A (zh) * 2012-07-13 2015-07-08 酵活有限公司 多价异多聚体支架设计和构建体
US10358479B2 (en) 2012-07-13 2019-07-23 Zymeworks Inc. Multivalent heteromultimer scaffold design and constructs
US11248037B2 (en) 2012-07-13 2022-02-15 Zymeworks Inc. Multivalent heteromultimer scaffold design and constructs
WO2014012082A3 (en) * 2012-07-13 2014-04-03 Zymeworks Inc. Multivalent heteromultimer scaffold design an constructs
US9388231B2 (en) 2012-07-13 2016-07-12 Zymeworks Inc. Multivalent heteromultimer scaffold design and constructs
US9345766B2 (en) 2012-08-30 2016-05-24 Merrimack Pharmaceuticals, Inc. Combination therapies comprising anti-ERBB3 agents
US10934341B2 (en) 2012-11-08 2021-03-02 Albumedix, Ltd. Albumin variants
US10501524B2 (en) 2012-11-08 2019-12-10 Albumedix Ltd Albumin variants
EP2931298A4 (en) * 2012-12-12 2016-07-06 Teva Pharma FUSION OF HUMAN GROWTH HORMONES AND ALBUMIN, AND FORMULATION THEREOF AND USE THEREOF
EP3318124A2 (en) 2013-02-16 2018-05-09 Albumedix A/S Pharmacokinetic animal model
WO2014125082A1 (en) 2013-02-16 2014-08-21 Novozymes Biopharma Dk A/S Pharmacokinetic animal model
US11072654B2 (en) 2014-07-17 2021-07-27 Novo Nordisk A/S Site directed mutagenesis of TREM-1 antibodies for decreasing viscosity
US10179814B2 (en) 2014-07-17 2019-01-15 Novo Nordisk A/S Site directed mutagenesis of TREM-1 antibodies for decreasing viscosity
US11510963B1 (en) 2015-02-03 2022-11-29 Amryt Endo, Inc. Method of treating diseases
US11338011B2 (en) 2015-02-03 2022-05-24 Amryt Endo, Inc. Method of treating diseases
US11857595B2 (en) 2015-02-03 2024-01-02 Amryt Endo, Inc. Method of treating diseases
US10633428B2 (en) 2015-08-20 2020-04-28 Albumedix Ltd Albumin variants and conjugates
US11634474B2 (en) 2015-09-08 2023-04-25 Jcr Pharmaceuticals Co., Ltd. Human serum albumin mutant
US10654912B2 (en) 2015-09-08 2020-05-19 Jcr Pharmaceuticals Co., Ltd. Human serum albumin mutant
US11046751B2 (en) 2015-09-08 2021-06-29 Jcr Pharmaceuticals Co., Ltd. Human serum albumin mutant
US10968267B2 (en) 2016-03-14 2021-04-06 Jcr Pharmaceuticals Co., Ltd. Serum albumin-20K growth hormone fusion protein
WO2018082758A1 (en) 2016-11-04 2018-05-11 Aarhus Universitet Identification and treatment of tumors characterized by an overexpression of the neonatal fc receptor
US11155618B2 (en) 2018-04-02 2021-10-26 Bristol-Myers Squibb Company Anti-TREM-1 antibodies and uses thereof
US11952420B2 (en) 2018-04-02 2024-04-09 Bristol-Myers Squibb Company Nucleic acids encoding anti-TREM-1 antibodies
US11919954B2 (en) 2018-04-02 2024-03-05 Bristol-Myers Squibb Company Anti-TREM-1 antibodies and uses thereof
WO2021044361A1 (en) 2019-09-06 2021-03-11 Novartis Ag Therapeutic fusion proteins
WO2021044360A1 (en) 2019-09-06 2021-03-11 Novartis Ag Therapeutic fusion proteins
WO2021044362A1 (en) 2019-09-06 2021-03-11 Novartis Ag Therapeutic fusion proteins
WO2021106016A1 (en) * 2019-11-27 2021-06-03 Revelations Biotech Pvt Ltd Nucleic acids, vectors, host cells and methods for production of beta-fructofuranosidase from aspergillus niger
WO2021106017A1 (en) * 2019-11-27 2021-06-03 Revelations Biotech Pvt Ltd Nucleic acids, vectors, host cells and methods for production of fructosyltransferase from aspergillus japonicus
WO2021111143A1 (en) 2019-12-04 2021-06-10 Albumedix Limited Methods and compositions produced thereby
US11890316B2 (en) 2020-12-28 2024-02-06 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods

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